U.S. patent number 10,676,437 [Application Number 16/218,759] was granted by the patent office on 2020-06-09 for fluorinated 4-(substituted amino)phenyl carbamate derivatives.
This patent grant is currently assigned to SciFluor Life Sciences, Inc.. The grantee listed for this patent is SciFluor Life Sciences, Inc.. Invention is credited to Ben C. Askew, D. Scott Edwards, Takeru Furuya.
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United States Patent |
10,676,437 |
Furuya , et al. |
June 9, 2020 |
Fluorinated 4-(substituted amino)phenyl carbamate derivatives
Abstract
The application relates to 4-(substituted amino)phenyl carbamate
derivatives, or pharmaceutically acceptable salts or solvates
thereof, as KCNQ2/3 potassium channel modulators, and methods of
their uses.
Inventors: |
Furuya; Takeru (Cambridge,
MA), Askew; Ben C. (Marshfield, MA), Edwards; D.
Scott (Bedford, MA) |
Applicant: |
Name |
City |
State |
Country |
Type |
SciFluor Life Sciences, Inc. |
Cambridge |
MA |
US |
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Assignee: |
SciFluor Life Sciences, Inc.
(Boston, MA)
|
Family
ID: |
66735141 |
Appl.
No.: |
16/218,759 |
Filed: |
December 13, 2018 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20190177274 A1 |
Jun 13, 2019 |
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Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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62597979 |
Dec 13, 2017 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07C
233/43 (20130101); C07D 211/44 (20130101); C07C
233/07 (20130101); C07D 217/02 (20130101); A61P
25/08 (20180101) |
Current International
Class: |
C07D
211/44 (20060101); C07C 233/07 (20060101); C07D
217/02 (20060101); A61P 25/08 (20060101); C07C
233/43 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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WO 01/01970 |
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Jan 2001 |
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WO |
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WO 2006/029623 |
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Mar 2006 |
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WO |
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WO 2008/024398 |
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Feb 2008 |
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WO |
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WO 2014/048165 |
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Apr 2014 |
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WO |
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WO 2017/214539 |
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Dec 2017 |
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WO |
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Primary Examiner: Shameem; Golam M
Attorney, Agent or Firm: Cooley LLP Erlacher; Heidi A. Chen;
Chen
Parent Case Text
RELATED APPLICATION
This application claims priority to and the benefit of U.S.
Provisional Application No. 62/597,979, filed on Dec. 13, 2017, the
entire contents of which are incorporated herein by reference.
Claims
The invention claimed is:
1. A compound of formula A: ##STR00031## or a pharmaceutically
acceptable salt or solvate thereof, wherein: X.sub.1 and X.sub.9
are each independently methyl or ethyl; X.sub.4 is H,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl; X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m, wherein the
phenyl is optionally substituted with one or more substituents
independently selected from deuterium, F, SF.sub.5, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F,
C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4 alkoxy substituted with
one or more F; or X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a 5- to 7-membered
heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O,
and S, wherein the heterocyclic ring is optionally substituted with
one or more substituents independently selected from deuterium, F,
SF.sub.5, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted
with one or more F, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
alkoxy substituted with one or more F, or two substituents attached
to adjacent carbon atoms on the heterocyclic ring, together with
the carbon atoms to which they are attached, form a phenyl
optionally substituted with one or more substituents independently
selected from deuterium, F, SF.sub.5, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl substituted with one or more F,
C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4 alkoxy substituted with
one or more F; each X.sub.5 is independently H, deuterium, F,
C.sub.1-C.sub.4 alkyl, or C.sub.1-C.sub.4 alkyl substituted with
one or more F; and m is 1, 2, or 3.
2. The compound of claim 1, being of formula Ia or Ib: ##STR00032##
or a pharmaceutically acceptable salt or solvate thereof.
3. The compound of claim 1, wherein X.sub.4 is H.
4. The compound of claim 1, wherein X.sub.4 is C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl.
5. The compound of claim 1, wherein X.sub.5 is
phenyl-(CX.sub.8X.sub.8), phenyl-(CX.sub.8X.sub.8).sub.2, or
phenyl-(CX.sub.8X.sub.8).sub.3, wherein the phenyl is optionally
substituted with one or more substituents independently selected
from deuterium, F, SF.sub.5, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, C.sub.1-C.sub.4 alkoxy, and
C.sub.1-C.sub.4 alkoxy substituted with one or more F.
6. The compound of claim 5, wherein X.sub.5 is
phenyl-(CX.sub.8X.sub.8).
7. The compound of claim 5, wherein the phenyl is substituted with
one or more substituents independently selected from F, CF.sub.3,
and OCF.sub.3.
8. The compound of claim 1, wherein X.sub.4 and X.sub.5, together
with the nitrogen atom to which they are attached, form a 5- to
7-membered heterocyclic ring comprising 1 or 2 heteroatoms selected
from N, O, and S, wherein the heterocyclic ring is optionally
substituted with one or more substituents independently selected
from deuterium, F, SF.sub.5, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, C.sub.1-C.sub.4 alkoxy, and
C.sub.1-C.sub.4 alkoxy substituted with one or more F.
9. The compound of claim 8, wherein the heterocyclic ring is
substituted with one or more substituents independently selected
from CH.sub.3 and OCH.sub.3.
10. The compound of claim 8, wherein the heterocyclic ring is
pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,
piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiapyranyl,
dioxanyl, morpholinyl, oxazinanyl, thiazinanyl, or oxathianyl.
11. The compound of claim 1, wherein X.sub.4 and X.sub.5, together
with the nitrogen atom to which they are attached, form a 5- to
7-membered heterocyclic ring substituted with two or more
substituents, wherein two substituents attached to adjacent carbon
atoms on the heterocyclic ring, together with the carbon atoms to
which they are attached, form a phenyl optionally substituted with
one or more substituents independently selected from deuterium, F,
SF.sub.5, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted
with one or more F, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
alkoxy substituted with one or more F.
12. The compound of claim 11, wherein X.sub.4 and X.sub.5, together
with the nitrogen atom to which they are attached, form a
heterocyclic ring selected from ##STR00033## wherein the nitrogen
atom is the nitrogen atom bonded to X.sub.4 and X.sub.5.
13. The compound of claim 1, being of formula IIa or IIb:
##STR00034## or a pharmaceutically acceptable salt or solvate
thereof, wherein: X.sub.4 is H, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl; t1 is 1, 2, 3,
4, or 5; each Z.sub.1 is independently selected from deuterium, F,
SF.sub.5, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted
with one or more F, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4
alkoxy substituted with one or more F; and m is 1, 2, or 3.
14. The compound of claim 1, being of formula IIIa or IIIb:
##STR00035## or a pharmaceutically acceptable salt or solvate
thereof, wherein: q is 1, 2, or 3; t2 is 1, 2, 3, or 4; and each
Z.sub.2 is independently selected from deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4 alkoxy
substituted with one or more F.
15. The compound of claim 1, being of formula IVa or IVb:
##STR00036## or a pharmaceutically acceptable salt or solvate
thereof, wherein: r is 1, 2, or 3; t3 is 1, 2, 3, or 4; and each
Z.sub.3 is independently selected from deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4 alkoxy
substituted with one or more F.
16. The compound of claim 1, being selected from the groups
consisting of ##STR00037## and pharmaceutically acceptable salts
and solvates thereof.
17. A pharmaceutical composition comprising at least one compound
of claim 1 or a pharmaceutically acceptable salt or solvate thereof
and one or more pharmaceutically acceptable carrier or excipient.
Description
BACKGROUND
Epilepsy is one of the most common chronic neurological disorders,
and affects approximately 50 million people worldwide. Epilepsy
patients have significantly increased morbidity, including closed
head injury, fractures, burns, dental injury and soft tissue
injury. Decline in or worsening of memory, cognition, depression
and sexual function and other lifestyle limitations occur
frequently in epilepsy patients. Epilepsy patients also have an
increased risk of mortality compared to the general population.
Although various pharmacologic agents are approved to treat
epilepsy, many patients are not adequately treated with the
currently available options. It is estimated that nearly a third of
patients with epilepsy have either intractable or uncontrolled
seizures or significant adverse side effects.
Ezogabine or retigabine, also known as ethyl
N-[2-amino-4-[(4-fluorophenyl) methylamino]phenyl]carbamate, is an
anticonvulsant used as a treatment for partial epilepsies.
Ezogabine works primarily as a potassium channel opener, i.e., by
activating KCNQ2/3 voltage-gated potassium channels in the brain.
Ezogabine was approved by the FDA and is marketed as Potiga.TM. and
Trobalt.TM.. U.S. Pat. No. 5,384,330 and WO 01/01970 describe
ezogabine and its use. The most common adverse events with
ezogabine are central nervous system effects, particularly
dizziness and somnolence. Occasional instances of urinary
difficulty may require surveillance. Recently, ezogabine has been
associated with skin discoloration and eye pigmentation changes in
patients. These more serious side-effects have resulted in the
marketing application holders and its removal from the market in
2017.
Because of the beneficial activities seen with ezogabine, there is
a continuing interest in developing new compounds to treat epilepsy
and other conditions ameliorated by KCNQ2/3 potassium channel
opening.
SUMMARY OF THE APPLICATION
The present application relates to a compound of formula A:
##STR00001## or a pharmaceutically acceptable salt or solvate
thereof, wherein the compound of formula A is disclosed in detail
herein below.
The application also relates to a pharmaceutical composition
comprising a compound of the present application, or a
pharmaceutically acceptable salt or solvate thereof, and a
pharmaceutically acceptable carrier.
The application also relates to a method of modulating a KCNQ2/3
potassium channel, comprising administering to a subject in need
thereof, a therapeutically effective amount of a compound of the
present application, or a pharmaceutically acceptable salt or
solvate thereof.
The application also relates to a compound of the present
application, or a pharmaceutically acceptable salt or solvate
thereof, for use in modulating a KCNQ2/3 potassium channel.
The application also relates to a compound of the present
application, or a pharmaceutically acceptable salt or solvate
thereof, for use in the manufacture of a medicament for modulating
a KCNQ2/3 potassium channel.
The present application also relates to use of a compound of the
present application, or a pharmaceutically acceptable salt or
solvate thereof, in the manufacture of a medicament for modulation
of a KCNQ2/3 potassium channel.
The application further relates to a method of treating or
preventing a disease or disorder which can be ameliorated by
KCNQ2/3 potassium channel opening, comprising administering to a
subject in need thereof, a therapeutically effective amount of a
compound of the present application, or a pharmaceutically
acceptable salt or solvate thereof.
The application also relates to a compound of the present
application, or a pharmaceutically acceptable salt or solvate
thereof, for use in treating or preventing a disease or disorder
which can be ameliorated by KCNQ2/3 potassium channel opening.
The application also relates to a compound of the present
application, or a pharmaceutically acceptable salt or solvate
thereof, for use in the manufacture of a medicament for treating or
preventing a disease or disorder which can be ameliorated by
KCNQ2/3 potassium channel opening.
The present application also relates to use of a compound of the
present application, or a pharmaceutically acceptable salt or
solvate thereof, in the manufacture of a medicament for the
treatment or prevention of a disease or disorder which can be
ameliorated by KCNQ2/3 potassium channel opening.
The application further relates to a method of treating or
preventing epilepsy, comprising administering to a subject in need
thereof, a therapeutically effective amount of a compound of the
present application, or a pharmaceutically acceptable salt or
solvate thereof.
The application also relates to a compound of the present
application, or a pharmaceutically acceptable salt or solvate
thereof, for use in treating or preventing epilepsy.
The application also relates to a compound of the present
application, or a pharmaceutically acceptable salt or solvate
thereof, for use in the manufacture of a medicament for treating or
preventing epilepsy.
The present application also relates to the use of a compound of
the present application, or a pharmaceutically acceptable salt or
solvate thereof, in the manufacture of a medicament for the
treatment or prevention of epilepsy.
Unless otherwise defined, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this application belongs. In the
case of conflict, the present specification, including definitions,
will control. In the specification, the singular forms also include
the plural unless the context clearly dictates otherwise. Although
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
application, suitable methods and materials are described below.
All publications, patent applications, patents, and other
references mentioned herein are incorporated by reference. The
references cited herein are not admitted to be prior art to the
present application. In addition, the materials, methods, and
examples are illustrative only and are not intended to be
limiting.
Other features and advantages of the application will be apparent
from the following detailed description and claims.
DETAILED DESCRIPTION OF THE APPLICATION
For purposes of the present application, the following definitions
will be used (unless expressly stated otherwise):
The term "a compound of the application" or "compounds of the
application" refers to any compound disclosed herein, e.g., a
compound of any of the formulae described herein, including formula
A, Ia, Ib, IIa, IIb, IIIa, IIIb, IVa, or IVb, and/or an individual
compound explicitly disclosed herein. Whenever the term is used in
the context of the present application it is to be understood that
the reference is being made to the free base, a deuterium labeled
compound, and the corresponding pharmaceutically acceptable salts
or solvates thereof, provided that such is possible and/or
appropriate under the circumstances.
The term "pharmaceutical" or "pharmaceutically acceptable" when
used herein as an adjective, means substantially non-toxic and
substantially non-deleterious to the recipient.
By "pharmaceutical formulation" it is further meant that the
carrier, solvent, excipient, and salt must be compatible with the
active ingredient of the formulation (e.g., a compound of the
application). It is understood by those of ordinary skill in this
art that the terms "pharmaceutical formulation" and "pharmaceutical
composition" are generally interchangeable, and they are so used
for the purposes of this application.
Some of the compounds of the present application may exist in
unsolvated as well as solvated forms such as, for example,
hydrates.
"Solvate" means a solvent addition form that contains either a
stoichiometric or non stoichiometric amounts of solvent. Some
compounds have a tendency to trap a fixed molar ratio of solvent
molecules in the crystalline solid state, thus forming a solvate.
If the solvent is water the solvate formed is a hydrate, when the
solvent is alcohol, the solvate formed is an alcoholate. Hydrates
are formed by the combination of one or more molecules of water
with one of the substances in which the water retains its molecular
state as H.sub.2O, such combination being able to form one or more
hydrate. In the hydrates, the water molecules are attached through
secondary valencies by intermolecular forces, in particular
hydrogen bridges. Solid hydrates contain water as so-called crystal
water in stoichiometric ratios, where the water molecules do not
have to be equivalent with respect to their binding state. Examples
of hydrates are sesquihydrates, monohydrates, dihydrates or
trihydrates. Equally suitable are the hydrates of salts of the
compounds of the application.
Physiologically acceptable, i.e., pharmaceutically compatible or
pharmaceutically acceptable, salts can be salts of the compounds of
the application with inorganic or organic acids. Preference is
given to salts with inorganic acids, such as, for example,
hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric
acid, or to salts with organic carboxylic or sulphonic acids, such
as, for example, acetic acid, trifluoroacetic acid, propionic acid,
maleic acid, fumaric acid, malic acid, citric acid, tartaric acid,
lactic acid, benzoic acid, or methanesulphonic acid,
ethanesulphonic acid, benzenesulphonic acid, toluenesulphonic acid
or naphthalenedisulphonic acid. Other pharmaceutically compatible
salts which may be mentioned are salts with customary bases, such
as, for example, alkali metal salts (for example sodium or
potassium salts), alkaline earth metal salts (for example calcium
or magnesium salts) or ammonium salts, derived from ammonia or
organic amines, such as, for example, diethylamine, triethylamine,
ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,
dihydroabietylamine or methylpiperidine. Representative salts
include the following: acetate, benzenesulfonate, benzoate,
bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate,
carbonate, chloride, clavulanate, citrate, dihydrochloride,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, oleate, oxalate, pamottle (embonate), palmitate,
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, sulfate, subacetate, succinate, tannate, tartrate,
teoclate, tosylate, triethiodide, and valerate.
The compounds of the application may contain one or more asymmetric
centers and can thus occur as racemates and racemic mixtures,
single enantiomers, diastereomeric mixtures and individual
diastereomers. Additional asymmetric centers may be present
depending upon the nature of the various substituents on the
molecule. Each such asymmetric center will independently produce
two optical isomers. It is intended that all of the possible
optical isomers and diastereomers in mixtures and as pure or
partially purified compounds are included within the ambit of the
application. The application is meant to comprehend all such
isomeric forms of these compounds.
The independent syntheses of these diastereomers or their
chromatographic separations may be achieved as known in the art by
appropriate modification of the methodology disclosed herein. Their
absolute stereochemistry may be determined by the X-ray
crystallography of crystalline products or crystalline
intermediates which are derivatized, if necessary, with a reagent
containing an asymmetric center of known absolute
configuration.
In the present specification, the structural formula of the
compound represents a certain isomer for convenience in some cases,
but the present application includes all isomers, such as
geometrical isomers, optical isomers based on an asymmetrical
carbon, stereoisomers, tautomers, and the like.
"Isomerism" means compounds that have identical molecular formulae
but differ in the sequence of bonding of their atoms or in the
arrangement of their atoms in space. Isomers that differ in the
arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed
"diastereoisomers", and stereoisomers that are non-superimposable
mirror images of each other are termed "enantiomers" or sometimes
optical isomers. A mixture containing equal amounts of individual
enantiomeric forms of opposite chirality is termed a "racemic
mixture".
"Chiral isomer" means a compound with at least one chiral center.
Compounds with more than one chiral center may exist either as an
individual diastereomer or as a mixture of diastereomers, termed
"diastereomeric mixture". When one chiral center is present, a
stereoisomer may be characterized by the absolute configuration (R
or S) of that chiral center. Absolute configuration refers to the
arrangement in space of the substituents attached to the chiral
center. The substituents attached to the chiral center under
consideration are ranked in accordance with the Sequence Rule of
Cahn, Ingold and Prelog. (Cahn et al., Angew. Chem. Inter. Edit.
1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413;
Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al.,
Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).
"Geometric isomer" means the diastereomers that owe their existence
to hindered rotation about double bonds. These configurations are
differentiated in their names by the prefixes cis and trans, or Z
and E, which indicate that the groups are on the same or opposite
side of the double bond in the molecule according to the
Cahn-Ingold-Prelog rules.
Furthermore, the structures and other compounds discussed in this
application include all atropic isomers thereof. "Atropic isomers"
are a type of stereoisomer in which the atoms of two isomers are
arranged differently in space. Atropic isomers owe their existence
to a restricted rotation caused by hindrance of rotation of large
groups about a central bond. Such atropic isomers typically exist
as a mixture, however as a result of recent advances in
chromatography techniques; it has been possible to separate
mixtures of two atropic isomers in select cases.
"Tautomer" is one of two or more structural isomers that exist in
equilibrium and is readily converted from one isomeric form to
another. This conversion results in the formal migration of a
hydrogen atom accompanied by a switch of adjacent conjugated double
bonds. Tautomers exist as a mixture of a tautomeric set in
solution. In solid form, usually one tautomer predominates. In
solutions where tautomerization is possible, a chemical equilibrium
of the tautomers will be reached. The exact ratio of the tautomers
depends on several factors, including temperature, solvent and pH.
The concept of tautomers that are interconvertable by
tautomerizations is called tautomerism.
Of the various types of tautomerism that are possible, two are
commonly observed. In keto-enol tautomerism a simultaneous shift of
electrons and a hydrogen atom occurs. Ring-chain tautomerism arises
as a result of the aldehyde group (--CHO) in a sugar chain molecule
reacting with one of the hydroxy groups (--OH) in the same molecule
to give it a cyclic (ring-shaped) form as exhibited by glucose.
Common tautomeric pairs are: ketone-enol, amide-nitrile,
lactam-lactim, amide-imidic acid tautomerism in heterocyclic rings
(e.g., in nucleobases such as guanine, thymine and cytosine),
amine-enamine and enamine-enamine. In one example,
##STR00002## are tautomers to each other.
It is to be understood that the compounds of the present
application may be depicted as different tautomers. It should also
be understood that when compounds have tautomeric forms, all
tautomeric forms are intended to be included in the scope of the
present application, and the naming of the compounds does not
exclude any tautomer form.
If desired, racemic mixtures of the compounds may be separated so
that the individual enantiomers are isolated. The separation can be
carried out by methods well known in the art, such as contacting a
racemic mixture of compounds with an enantiomerically pure compound
to form a diastereomeric mixture, followed by separation of the
individual diastereomers by standard methods, such as fractional
crystallization or chromatography. The diastereomeric mixture is
often a mixture of diasteriomeric salts formed by contacting a
racemic mixture of compounds with an enantiomerically pure acid or
base. The diastereomeric derivatives may then be converted to the
pure enantiomers by cleavage of the added chiral residue. The
racemic mixture of the compounds can also be separated directly by
chromatographic methods utilizing chiral stationary phases, which
are well known in the art.
The application also includes one or more metabolites of a compound
of the application.
The present application also comprehends deuterium labeled
compounds of each of the formulae described herein or the
individual compounds specifically disclosed, wherein a hydrogen
atom is replaced by a deuterium atom. The deuterium labeled
compounds comprise a deuterium atom having an abundance of
deuterium that is substantially greater than the natural abundance
of deuterium, e.g., 0.015%.
The term "deuterium enrichment factor" as used herein means the
ratio between the deuterium abundance and the natural abundance of
a deuterium. In one aspect, a compound of the application has a
deuterium enrichment factor for each deuterium atom of at least
3500 (52.5% deuterium incorporation at each deuterium atom), at
least 4000 (60% deuterium incorporation), at least 4500 (67.5%
deuterium incorporation), at least 5000 (75% deuterium), at least
5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium
incorporation), at least 6333.3 (95% deuterium incorporation), at
least 6466.7 (97% deuterium incorporation), at least 6600 (99%
deuterium incorporation), or at least 6633.3 (99.5% deuterium
incorporation).
Deuterium labeled compounds can be prepared using any of a variety
of art-recognized techniques. For example, deuterium labeled
compounds of each of the formulae described herein or the compounds
listed in Table 1 can generally be prepared by carrying out the
procedures described herein, by substituting a readily available
deuterium labeled reagent for a non-deuterium labeled reagent.
A compound of the application or a pharmaceutically acceptable salt
or solvate thereof that contains the aforementioned deuterium
atom(s) is within the scope of the application. Further,
substitution with deuterium, i.e., .sup.2H, can afford certain
therapeutic advantages resulting from greater metabolic stability,
for example, increased in vivo half-life and/or reduced dosage
requirements.
As used herein, the term "treat", "treating", or "treatment"
herein, is meant decreasing the symptoms, markers, and/or any
negative effects of a disease, disorder or condition in any
appreciable degree in a patient who currently has the condition.
The term "treat", "treating", or "treatment" includes alleviating
symptoms of a disease, disorder, or condition, e.g., alleviating
the symptoms of epilepsy. In some embodiments, treatment may be
administered to a subject who exhibits only early signs of the
condition for the purpose of decreasing the risk of developing the
disease, disorder, and/or condition.
As used herein, the term "prevent", "prevention", or "preventing"
refers to any method to partially or completely prevent or delay
the onset of one or more symptoms or features of a disease,
disorder, and/or condition. Prevention may be administered to a
subject who does not exhibit signs of a disease, disorder, and/or
condition.
As used herein, "subject" means a human or animal (in the case of
an animal, more typically a mammal). In one embodiment, the subject
is a human. In one embodiment, the subject is a male. In one
embodiment, the subject is a female.
As used herein, the term a "fluorinated derivative" is a derivative
compound that has the same chemical structure as the original
compound, except that at least one atom is replaced with a fluorine
atom or with a group of atoms containing at least one fluorine
atom.
The problem to be solved by the present application is the
identification of novel compounds for the treatment and/or
prevention of epilepsy and/or other diseases or disorders
ameliorated by KCNQ2/3 potassium channel opening. Although drugs
for epilepsy and related disorders are available, these drugs are
often not suitable for many patients for a variety of reasons. Many
epilepsy drugs are associated with adverse effects. For example,
many of the available epilepsy drugs are believed to significantly
increase the risk of birth defects if taken during the first
trimester of pregnancy. Other adverse side effects include urinary
retention, neuro-psychiatric symptoms including hallucinations and
psychosis, dizziness and somnolence, QT-prolonging effect, and
increased risk of suicidal behavior and ideation. Some epilepsy
drugs require administration of high doses due to extensive
metabolism into inactive or less potent metabolites. The present
application provides the solution of new fluorinated 4-(substituted
amino)phenylcarbamate compounds for treating epilepsy and other
diseases or disorders ameliorated by KCNQ2/3 potassium channel
opening. The compounds described herein have the advantage of
providing improved potency, selectivity, tissue penetration,
half-life, and/or metabolic stability.
Compounds of the Application
The present application relates to a compound of formula A:
##STR00003## or a pharmaceutically acceptable salt or solvate
thereof, wherein:
X.sub.1 and X.sub.9 are each independently methyl or ethyl;
X.sub.4 is H, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl;
X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m, wherein the phenyl is
optionally substituted with one or more substituents independently
selected from deuterium, F, SF.sub.5, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkyl substituted with one or more F,
C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4 alkoxy substituted with
one or more F; or
X.sub.4 and X.sub.5, together with the nitrogen atom to which they
are attached, form a 5- to 7-membered heterocyclic ring comprising
1 or 2 heteroatoms selected from N, O, and S, wherein the
heterocyclic ring is optionally substituted with one or more
substituents independently selected from deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, C.sub.1-C.sub.4 alkoxy, and C.sub.1-C.sub.4 alkoxy
substituted with one or more F, or two substituents attached to
adjacent carbon atoms on the heterocyclic ring, together with the
carbon atoms to which they are attached, form a phenyl optionally
substituted with one or more substituents independently selected
from deuterium, F, SF.sub.5, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkyl substituted with one or more F, C.sub.1-C.sub.4 alkoxy, and
C.sub.1-C.sub.4 alkoxy substituted with one or more F;
each X.sub.5 is independently H, deuterium, F, C.sub.1-C.sub.4
alkyl, or C.sub.1-C.sub.4 alkyl substituted with one or more F;
and
m is 1, 2, or 3.
In one embodiment, the compound of formula A is of formula Ia:
##STR00004## or a pharmaceutically acceptable salt or solvate
thereof, wherein X.sub.4, X.sub.5, X.sub.8, and m are each as
defined above in formula A.
In one embodiment, the compound of formula A is of formula Ib:
##STR00005## or a pharmaceutically acceptable salt or solvate
thereof, wherein X.sub.4, X.sub.5, X.sub.8, and m are each as
defined above in formula A.
For a compound of formula A, Ia, or Ib, X.sub.1, X.sub.4, X.sub.5,
X.sub.8, X.sub.9, and m can each be, where applicable, selected
from the groups described herein below, and any group described
herein for any of X.sub.1, X.sub.4, X.sub.5, X.sub.8, X.sub.9, and
m can be combined, where applicable, with any group described
herein for one or more of the remainder of X.sub.1, X.sub.4,
X.sub.5, X.sub.8, X.sub.9, and m.
In one embodiment, X.sub.1 and X.sub.9 are each methyl.
In one embodiment, X.sub.1 and X.sub.9 are each ethyl.
In one embodiment, one of X.sub.1 and X.sub.9 is methyl and the
other is ethyl.
In one embodiment, X.sub.4 is H.
In one embodiment, X.sub.4 is C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl.
In one embodiment, X.sub.4 is selected from methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, and t-butyl.
In one embodiment, X.sub.4 is selected from ethenyl, propenyl
(e.g., 1-propenyl or 2-propenyl), butenyl (e.g., 1-butenyl,
2-butenyl, or 3-butenyl), pentenyl (e.g., 1-pentenyl, 2-pentenyl,
3-pentenyl, or 4-pentenyl), and hexenyl (e.g., 1-hexenyl,
2-hexenyl, 3-hexenyl, 4-hexenyl, or 5-hexenyl). In one embodiment,
X.sub.4 is 1-propenyl or 2-propenyl.
In one embodiment, X.sub.4 is selected from ethynyl, propynyl
(e.g., 1-propynyl or 2-propynyl), butynyl (e.g., 1-butynyl,
2-butynyl, or 3-butynyl), pentynyl (e.g., 1-pentynyl, 2-pentynyl,
3-pentynyl, or 4-pentynyl), and hexynyl (e.g., 1-hexynyl,
2-hexynyl, 3-hexynyl, 4-hexynyl, or 5-hexynyl). In one embodiment,
X.sub.4 is 1-propynyl or 2-propynyl.
In one embodiment, X.sub.5 is phenyl-(CX.sub.8X.sub.8),
phenyl-(CX.sub.8X.sub.8).sub.2, or phenyl-(CX.sub.8X.sub.8).sub.3,
wherein the phenyl is optionally substituted with one or more
substituents independently selected from deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from F, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F).
In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F, C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more groups independently selected from F, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, CF.sub.3, and OCF.sub.3.
In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F and C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F). In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
SF.sub.5, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more groups independently
selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and CF.sub.3.
In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from F, SF.sub.5, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In
one embodiment, the phenyl is substituted with one or more
substituents independently selected from F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more groups independently selected from F, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and OCF.sub.3.
In one embodiment, the phenyl is substituted with one or more
substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl)
and C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy). In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3, and
OCH.sub.2CH.sub.3. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from CH.sub.3
and CH.sub.2CH.sub.3. In one embodiment, the phenyl is substituted
with one or more CH.sub.3. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from OCH.sub.3 and OCH.sub.2CH.sub.3. In one embodiment, the phenyl
is substituted with one or more OCH.sub.3.
In one embodiment, the substituent is attached at the para-position
on the phenyl ring. In one embodiment, the substituent(s) are
attached at the meta-position(s) on the phenyl ring. In one
embodiment, the substituent(s) are attached at the
ortho-position(s) on the phenyl ring.
In one embodiment, X.sub.5 is 2-fluoro-benzyl. In one embodiment,
X.sub.5 is 3-fluoro-benzyl. In one embodiment, X.sub.5 is
4-fluoro-benzyl. In one embodiment, X.sub.5 is 2-fluoro-benzyl. In
one embodiment, X.sub.5 is 3-fluoro-benzyl. In one embodiment,
X.sub.5 is 2-trifluoromethyl-benzyl. In one embodiment, X.sub.5 is
3-trifluoromethyl-benzyl. In one embodiment, X.sub.5 is
4-trifluoromethyl-benzyl. In one embodiment, X.sub.5 is
2-trifluoromethoxy-benzyl. In one embodiment, X.sub.5 is
3-trifluoromethoxy-benzyl. In one embodiment, X.sub.5 is
4-trifluoromethoxy-benzyl.
In one embodiment, each X.sub.8 is H. In one embodiment, at least
one X.sub.8 is deuterium, F, C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl), or
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F). In one embodiment, at least one
X.sub.8 is deuterium. In one embodiment, at least one X.sub.8 is F,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), or C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, at least one X.sub.8 is C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl) or C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F). In one
embodiment, at least one X.sub.8 is F or C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F). In one embodiment, at least one X.sub.8 is
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl). In one embodiment, at least one
X.sub.8 is C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F). In one
embodiment, at least one X.sub.8 is F.
In one embodiment, X.sub.4 and X.sub.8, together with the nitrogen
atom to which they are attached, form a 5- to 7-membered
heterocyclic ring comprising 1 or 2 heteroatoms selected from N, O,
and S (e.g., pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,
oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl,
piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiapyranyl,
dioxanyl, morpholinyl, oxazinanyl, thiazinanyl, or oxathianyl). In
one embodiment, X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a 5- to 7-membered
heterocyclic ring comprising 1 heteroatom selected from N, O, and
S. In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- or 6-membered
heterocyclic ring comprising 1 heteroatom selected from N, O, and
S. In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- or 6-membered
heterocyclic ring comprising 1 heteroatom selected from N and O. In
one embodiment, X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a pyrrolidinyl or piperidinyl
ring.
In one embodiment, X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a 5- to 7-membered
heterocyclic ring optionally substituted with one or more
substituents independently selected from deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from F, C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the heterocyclic ring is substituted
with one or more substituents independently selected from F,
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), and C.sub.1-C.sub.4 alkoxy
substituted with one or more F (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from F, SF.sub.5, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3,
OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the heterocyclic ring is
substituted with one or more groups independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and
OCH.sub.2F. In one embodiment, the heterocyclic ring is substituted
with one or more substituents independently selected from F,
CF.sub.3, and OCF.sub.3. In one embodiment, the heterocyclic ring
is substituted with one or more substituents independently selected
from F and C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F). In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
heterocyclic ring is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F.
In one embodiment, the heterocyclic ring is substituted with one or
more substituents independently selected from F and CF.sub.3. In
one embodiment, the heterocyclic ring is substituted with one or
more substituents independently selected from F and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from F, SF.sub.5, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from F, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
heterocyclic ring is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from F and OCF.sub.3. In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and
C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,
butoxy, i-butoxy, or t-butoxy). In one embodiment, the heterocyclic
ring is substituted with one or more substituents independently
selected from CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3, and
OCH.sub.2CH.sub.3. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from CH.sub.3 and CH.sub.2CH.sub.3. In one embodiment, the
heterocyclic ring is substituted with one or more CH.sub.3. In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from OCH.sub.3 and
OCH.sub.2CH.sub.3. In one embodiment, the heterocyclic ring is
substituted with one or more OCH.sub.3.
In one embodiment, X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a 5- to 7-membered
heterocyclic ring substituted with two or more substituents,
wherein two substituents attached to adjacent carbon atoms on the
heterocyclic ring, together with the carbon atoms to which they are
attached, form a phenyl optionally substituted with one or more
substituents independently selected from deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from F, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), and C.sub.1-C.sub.4 alkoxy substituted with one or more F
(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, SF.sub.5, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more groups independently selected from F, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, CF.sub.3, and OCF.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more groups independently
selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and CF.sub.3. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and C.sub.1-C.sub.4 alkoxy substituted with one or
more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In
one embodiment, the phenyl is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and OCF.sub.3. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl) and C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, and OCH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CH.sub.3 and CH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more CH.sub.3. In
one embodiment, the phenyl is substituted with one or more
substituents independently selected from OCH.sub.3 and
OCH.sub.2CH.sub.3. In one embodiment, the phenyl is substituted
with one or more OCH.sub.3.
In one embodiment, X.sub.4 and X.sub.5, together with the nitrogen
atom to which they are attached, form a heterocyclic ring selected
from
##STR00006## wherein the nitrogen atom is the nitrogen atom bonded
to X.sub.4 and X.sub.5. In one embodiment, X.sub.4 and X.sub.5,
together with the nitrogen atom to which they are attached,
form
##STR00007## wherein the nitrogen atom is the nitrogen atom bonded
to X.sub.4 and X.sub.5.
In one embodiment, m is 1. In one embodiment, m is 2. In one
embodiment, m is 3.
Any of the substituent groups described above for any of X.sub.1,
X.sub.4, X.sub.5, X.sub.8, X.sub.9, and m can be combined with any
of the substituent groups described above for one or more of the
remainder of X.sub.1, X.sub.4, X.sub.5, X.sub.8, X.sub.9, and
m.
(1a) In one embodiment, X.sub.4 is C.sub.1-C.sub.4 alkyl, and
X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m. In one embodiment, the
phenyl is optionally substituted with one or more substituents
independently selected from deuterium, F, SF.sub.5, C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more groups independently selected from F, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, CF.sub.3, and OCF.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more groups independently
selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and CF.sub.3. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and C.sub.1-C.sub.4 alkoxy substituted with one or
more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In
one embodiment, the phenyl is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and OCF.sub.3. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl) and C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, and OCH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CH.sub.3 and CH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more CH.sub.3. In
one embodiment, the phenyl is substituted with one or more
substituents independently selected from OCH.sub.3 and
OCH.sub.2CH.sub.3. In one embodiment, the phenyl is substituted
with one or more OCH.sub.3.
(1b) In one embodiment, X.sub.4 is C.sub.2-C.sub.6 alkenyl, and
X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m. In one embodiment, the
phenyl is optionally substituted with one or more substituents
independently selected from deuterium, F, SF.sub.5, C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more groups independently selected from F, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, CF.sub.3, and OCF.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more groups independently
selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and CF.sub.3. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and C.sub.1-C.sub.4 alkoxy substituted with one or
more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In
one embodiment, the phenyl is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and OCF.sub.3. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl) and C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, and OCH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CH.sub.3 and CH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more CH.sub.3. In
one embodiment, the phenyl is substituted with one or more
substituents independently selected from OCH.sub.3 and
OCH.sub.2CH.sub.3. In one embodiment, the phenyl is substituted
with one or more OCH.sub.3.
(1c) In one embodiment, X.sub.4 is C.sub.2-C.sub.6 alkynyl, and
X.sub.5 is phenyl-(CX.sub.8X.sub.8).sub.m. In one embodiment, the
phenyl is optionally substituted with one or more substituents
independently selected from deuterium, F, SF.sub.5, C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, C.sub.1-C.sub.4
alkyl substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more groups independently selected from F, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, CF.sub.3, and OCF.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more groups independently
selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and CF.sub.3. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and C.sub.1-C.sub.4 alkoxy substituted with one or
more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In
one embodiment, the phenyl is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and OCF.sub.3. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl) and C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, and OCH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CH.sub.3 and CH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more CH.sub.3. In
one embodiment, the phenyl is substituted with one or more
substituents independently selected from OCH.sub.3 and
OCH.sub.2CH.sub.3. In one embodiment, the phenyl is substituted
with one or more OCH.sub.3.
(1d) In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- to 7-membered
heterocyclic ring comprising 1 to 2 heteroatoms selected from N, O,
and S, optionally substituted with one or more substituents
independently selected from deuterium, F, SF.sub.5, C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl), C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F), C.sub.1-C.sub.4
alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the heterocyclic ring is substituted
with one or more substituents independently selected from F,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from F, C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), and C.sub.1-C.sub.4 alkoxy substituted with
one or more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the heterocyclic ring is substituted
with one or more substituents independently selected from F,
SF.sub.5, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the heterocyclic ring is
substituted with one or more groups independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and
OCH.sub.2F. In one embodiment, the heterocyclic ring is substituted
with one or more substituents independently selected from F,
CF.sub.3, and OCF.sub.3. In one embodiment, the heterocyclic ring
is substituted with one or more substituents independently selected
from F and C.sub.1-C.sub.4 alkyl substituted with one or more F
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl,
each of which is substituted with one or more F). In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
heterocyclic ring is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F.
In one embodiment, the heterocyclic ring is substituted with one or
more substituents independently selected from F and CF.sub.3. In
one embodiment, the heterocyclic ring is substituted with one or
more substituents independently selected from F and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from F, SF.sub.5, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from F, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
heterocyclic ring is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from F and OCF.sub.3.
In one embodiment, the heterocyclic ring is substituted with one or
more substituents independently selected from C.sub.1-C.sub.4 alkyl
(e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl)
and C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy). In one embodiment, the
heterocyclic ring is substituted with one or more substituents
independently selected from CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3,
and OCH.sub.2CH.sub.3. In one embodiment, the heterocyclic ring is
substituted with one or more substituents independently selected
from CH.sub.3 and CH.sub.2CH.sub.3. In one embodiment, the
heterocyclic ring is substituted with one or more CH.sub.3. In one
embodiment, the heterocyclic ring is substituted with one or more
substituents independently selected from OCH.sub.3 and
OCH.sub.2CH.sub.3. In one embodiment, the heterocyclic ring is
substituted with one or more OCH.sub.3.
(1e) In one embodiment, X.sub.4 and X.sub.5, together with the
nitrogen atom to which they are attached, form a 5- to 7-membered
heterocyclic ring substituted with two or more substituents,
wherein two substituents attached to adjacent carbon atoms on the
heterocyclic ring, together with the carbon atoms to which they are
attached, form a phenyl optionally substituted with one or more
substituents independently selected from deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from F, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), and C.sub.1-C.sub.4 alkoxy substituted with one or more F
(e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, SF.sub.5, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more groups independently selected from F, CF.sub.3,
CHF.sub.2, CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F, CF.sub.3, and OCF.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and C.sub.1-C.sub.4 alkyl substituted
with one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F). In one embodiment, the phenyl is substituted with one or more
substituents independently selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, the phenyl is substituted
with one or more substituents independently selected from F,
CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more groups independently
selected from F, CF.sub.3, CHF.sub.2, and CH.sub.2F. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from F and CF.sub.3. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and C.sub.1-C.sub.4 alkoxy substituted with one or
more F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy,
i-butoxy, or t-butoxy, each of which is substituted with one or
more F). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F, OCF.sub.3, OCHF.sub.2, OCH.sub.2F,
OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In
one embodiment, the phenyl is substituted with one or more groups
independently selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F,
OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one embodiment, the
phenyl is substituted with one or more substituents independently
selected from F and OCF.sub.3. In one embodiment, the phenyl is
substituted with one or more substituents independently selected
from C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl) and C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy). In one embodiment, the phenyl is substituted with one or
more substituents independently selected from CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, and OCH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more substituents
independently selected from CH.sub.3 and CH.sub.2CH.sub.3. In one
embodiment, the phenyl is substituted with one or more CH.sub.3. In
one embodiment, the phenyl is substituted with one or more
substituents independently selected from OCH.sub.3 and
OCH.sub.2CH.sub.3. In one embodiment, the phenyl is substituted
with one or more OCH.sub.3.
(2a) In one embodiment, m is 1.
(2b) In one embodiment, m is 2.
(2c) In one embodiment, m is 3.
(3a) In one embodiment, each X.sub.8 is H.
(3b) In one embodiment, at least one X.sub.8 is deuterium.
(3c) In one embodiment, at least one X.sub.8 is C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 alkyl substituted with one or more F, or
F.
(4a) In one embodiment, X.sub.1 is methyl, and X.sub.9 is
methyl.
(4b) In one embodiment, X.sub.1 is methyl, and X.sub.9 is
ethyl.
(4c) In one embodiment, X.sub.1 is ethyl, and X.sub.9 is ethyl.
(A1a) In one embodiment, X.sub.4 and X.sub.5 are each as defined in
(1a), and m is as defined in any one of (2a)-(2c). In a further
embodiment, m is as defined in (2a).
(A1b) In one embodiment, X.sub.4 and X.sub.5 are each as defined in
(1b), and m is as defined in any one of (2a)-(2c). In a further
embodiment, m is as defined in (2a).
(A1c) In one embodiment, X.sub.4 and X.sub.5 are each as defined in
(1c), and m is as defined in any one of (2a)-(2c). In a further
embodiment, m is as defined in (2a).
(A1d) In one embodiment, X.sub.4 and X.sub.5 are each as defined in
(1d), and m is as defined in any one of (2a)-(2c). In a further
embodiment, m is as defined in (2a).
(A1e) In one embodiment, X.sub.4 and X.sub.5 are each as defined in
(1e), and m is as defined in any one of (2a)-(2c). In a further
embodiment, m is as defined in (2a).
(B1a) In one embodiment, X.sub.4, X.sub.5, and m are each as
defined in any one of (A1a)-(A1e), and X.sub.8 is as defined in
(3a).
(B1b) In one embodiment, X.sub.4, X.sub.5, and m are each as
defined in any one of (A1a)-(A1e), and X.sub.8 is as defined in
(3b).
(B1c) In one embodiment, X.sub.4, X.sub.5, and m are each as
defined in any one of (A1a)-(A1e), and X.sub.8 is as defined in
(3c).
(C1a) In one embodiment, X.sub.4, X.sub.5, X.sub.8, and m are each
as defined in any one of (B1a)-(B1c), and X.sub.1 and X.sub.9 are
as defined in (4a).
(C1b) In one embodiment, X.sub.4, X.sub.5, X.sub.8, and m are each
as defined in any one of (B1a)-(B1c), and X.sub.1 and X.sub.9 are
as defined in (4b).
(C1c) In one embodiment, X.sub.4, X.sub.5, X.sub.8, and m are each
as defined in any one of (B1a)-(B1c), and X.sub.1 and X.sub.9 are
as defined in (4c).
In one embodiment, the compound of formula A is of formula IIa or
IIb:
##STR00008## or a pharmaceutically acceptable salt or solvate
thereof, wherein:
X.sub.4 and m are each as defined above in formula A;
t1 is 1, 2, 3, 4, or 5; and
each Z.sub.1 is independently deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 alkoxy
substituted with one or more F.
For a compound of formula IIa or IIb, t1 and Z.sub.1 can each be,
where applicable, selected from the groups described herein below,
and any group described herein for any of t1 and Z.sub.1 can be
combined, where applicable, with any group described herein for the
remainder of t1 and Z.sub.1.
In one embodiment, t1 is 1, 2, or 3. In one embodiment, t1 is 1 or
2. In one embodiment, t1 is 1. In one embodiment, t1 is 2. In one
embodiment, t1 is 3. In one embodiment, t1 is 4. In one embodiment,
t1 is 5.
In one embodiment, at least one Z.sub.1 is selected from deuterium,
F, SF.sub.5, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.1 is selected from F,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, at least one
Z.sub.1 is selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.1 is selected from F,
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), and C.sub.1-C.sub.4 alkoxy
substituted with one or more F (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, at least one
Z.sub.1 is selected from F, SF.sub.5, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.1 is selected from F, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.1 is selected from F, CF.sub.3, CHF.sub.2,
CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, at least one Z.sub.1 is selected from F, CF.sub.3, and
OCF.sub.3. In one embodiment, at least one Z.sub.1 is selected from
F and C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each
of which is substituted with one or more F). In one embodiment, at
least one Z.sub.1 is selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, at least one Z.sub.1 is
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.1 is selected from F, CF.sub.3, CHF.sub.2, and
CH.sub.2F. In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F and CF.sub.3. In
one embodiment, at least one Z.sub.1 is selected from F and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.1 is selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.1 is selected from F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, at least one Z.sub.1 is
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCHF.sub.2, and OCH.sub.2F. In one embodiment, at least one Z.sub.1
is selected from F and OCF.sub.3. In one embodiment, at least one
Z.sub.1 is F. In one embodiment, at least one Z.sub.1 is CF.sub.3.
In one embodiment, at least one Z.sub.1 is OCF.sub.3. In one
embodiment, at least one Z.sub.1 is selected from C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl) and C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy). In one
embodiment, at least one Z.sub.1 is selected from CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, and OCH.sub.2CH.sub.3. In one
embodiment, at least one Z.sub.1 is selected from CH.sub.3 and
CH.sub.2CH.sub.3. In one embodiment, at least one Z.sub.1 is
CH.sub.3. In one embodiment, at least one Z.sub.1 is selected from
OCH.sub.3 and OCH.sub.2CH.sub.3. In one embodiment, at least one
Z.sub.1 is OCH.sub.3.
For a compound of formula IIa or IIb, X.sub.4 and m can each be
selected from any of the substituents described above in formula A,
and any of the substituents described above for any of X.sub.4 and
m can be combined with any of the substituents described above for
one or more of the remainder of X.sub.4 and m, and can further be
combined with any of the substituents described for any of t1 and
Z.sub.1.
In one embodiment, t1 is 1, and Z.sub.1 is F, CF.sub.3, or
OCF.sub.3. In one embodiment, t1 is 1, and Z.sub.1 is F. In one
embodiment, t1 is 1, and Z.sub.1 is CF.sub.3. In one embodiment, t1
is 1, and Z.sub.1 is OCF.sub.3.
In one embodiment, t1 is 1, Z.sub.1 is F, CF.sub.3, or OCF.sub.3,
and m is 1. In one embodiment, t1 is 1, Z.sub.1 is F, and m is 1.
In one embodiment, t1 is 1, Z.sub.1 is CF.sub.3, and m is 1. In one
embodiment, t1 is 1, Z.sub.1 is OCF.sub.3, and m is 1.
In one embodiment, t1 is 1, Z.sub.1 is F, CF.sub.3, or OCF.sub.3, m
is 1, and X.sub.4 is H. In one embodiment, t1 is 1, Z.sub.1 is F, m
is 1, and X.sub.4 is H. In one embodiment, t1 is 1, Z.sub.1 is
CF.sub.3, m is 1, and X.sub.4 is H. In one embodiment, t1 is 1,
Z.sub.1 is OCF.sub.3, m is 1, and X.sub.4 is H.
In one embodiment, t1 is 1, and Z.sub.1 is CH.sub.3 or OCH.sub.3.
In one embodiment, t1 is 1, and Z.sub.1 is CH.sub.3. In one
embodiment, t1 is 1, and Z.sub.1 is OCH.sub.3.
In one embodiment, t1 is 1, and Z.sub.1 is CH.sub.3 or OCH.sub.3,
and m is 1. In one embodiment, t1 is 1, and Z.sub.1 is CH.sub.3,
and m is 1. In one embodiment, t1 is 1, and Z.sub.1 is OCH.sub.3,
and m is 1.
In one embodiment, t1 is 1, and Z.sub.1 is CH.sub.3 or OCH.sub.3, m
is 1, and X.sub.4 is H. In one embodiment, t1 is 1, and Z.sub.1 is
CH.sub.3, m is 1, and X.sub.4 is H. In one embodiment, t1 is 1, and
Z.sub.1 is OCH.sub.3, m is 1, and X.sub.4 is H.
In one embodiment, the compound of formula A is of formula IIIa or
IIIb:
##STR00009## or a pharmaceutically acceptable salt or solvate
thereof, wherein:
q is 1, 2, or 3;
t2 is 1, 2, 3, or 4; and
each Z.sub.2 is independently deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 alkoxy
substituted with one or more F.
For a compound of formula IIIa or IIIb, q, t2 and Z.sub.2 can each
be, where applicable, selected from the groups described herein
below, and any group described herein for any of q, t2 and Z.sub.2
can be combined, where applicable, with any group described herein
for the remainder of q, t2 and Z.sub.2.
In one embodiment, q is 1. In one embodiment, q is 2. In one
embodiment, q is 3.
In one embodiment, t2 is 1. In one embodiment, t2 is 2. In one
embodiment, t2 is 3. In one embodiment, t2 is 4.
In one embodiment, at least one Z.sub.2 is selected from deuterium,
F, SF.sub.5, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.2 is selected from F,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, at least one
Z.sub.2 is selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.2 is selected from F,
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), and C.sub.1-C.sub.4 alkoxy
substituted with one or more F (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, at least one
Z.sub.2 is selected from F, SF.sub.5, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.2 is selected from F, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.2 is selected from F, CF.sub.3, CHF.sub.2,
CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, at least one Z.sub.2 is selected from F, CF.sub.3, and
OCF.sub.3. In one embodiment, at least one Z.sub.2 is selected from
F and C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each
of which is substituted with one or more F). In one embodiment, at
least one Z.sub.2 is selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, at least one Z.sub.2 is
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.2 is selected from F, CF.sub.3, CHF.sub.2, and
CH.sub.2F. In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F and CF.sub.3. In
one embodiment, at least one Z.sub.2 is selected from F and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.2 is selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.2 is selected from F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, at least one Z.sub.2 is
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCHF.sub.2, and OCH.sub.2F. In one embodiment, at least one Z.sub.2
is selected from F and OCF.sub.3. In one embodiment, at least one
Z.sub.2 is F. In one embodiment, at least one Z.sub.2 is CF.sub.3.
In one embodiment, at least one Z.sub.2 is OCF.sub.3. In one
embodiment, at least one Z.sub.2 is selected from C.sub.1-C.sub.4
alkyl (e.g., methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or
t-butyl) and C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy). In one
embodiment, at least one Z.sub.2 is selected from CH.sub.3,
CH.sub.2CH.sub.3, OCH.sub.3, and OCH.sub.2CH.sub.3. In one
embodiment, at least one Z.sub.2 is selected from CH.sub.3 and
CH.sub.2CH.sub.3. In one embodiment, at least one Z.sub.2 is
CH.sub.3. In one embodiment, at least one Z.sub.2 is selected from
OCH.sub.3 and OCH.sub.2CH.sub.3. In one embodiment, at least one
Z.sub.2 is OCH.sub.3.
In one embodiment, the compound of formula A is of formula IVa or
IVb:
##STR00010## or a pharmaceutically acceptable salt or solvate
thereof, wherein:
r is 1, 2, or 3;
t3 is 1, 2, 3, or 4; and
each Z.sub.3 is independently deuterium, F, SF.sub.5,
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkyl substituted with one
or more F, C.sub.1-C.sub.4 alkoxy, or C.sub.1-C.sub.4 alkoxy
substituted with one or more F.
For a compound of formula IVa or IVb, r, t3 and Z.sub.3 can each
be, where applicable, selected from the groups described herein
below, and any group described herein for any of q, t2 and Z.sub.3
can be combined, where applicable, with any group described herein
for the remainder of q, t2 and Z.sub.3.
In one embodiment, r is 1. In one embodiment, r is 2. In one
embodiment, r is 3.
In one embodiment, t3 is 1. In one embodiment, t3 is 2. In one
embodiment, t3 is 3. In one embodiment, t3 is 4.
In one embodiment, at least one Z.sub.3 is selected from deuterium,
F, SF.sub.5, C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl
substituted with one or more F (e.g., methyl, ethyl, propyl,
i-propyl, butyl, i-butyl, or t-butyl, each of which is substituted
with one or more F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy), and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.3 is selected from F,
C.sub.1-C.sub.4 alkyl (e.g., methyl, ethyl, propyl, i-propyl,
butyl, i-butyl, or t-butyl), C.sub.1-C.sub.4 alkyl substituted with
one or more F (e.g., methyl, ethyl, propyl, i-propyl, butyl,
i-butyl, or t-butyl, each of which is substituted with one or more
F), C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy), and C.sub.1-C.sub.4
alkoxy substituted with one or more F (e.g., methoxy, ethoxy,
propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, at least one
Z.sub.3 is selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl),
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), C.sub.1-C.sub.4 alkoxy (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy), and C.sub.1-C.sub.4 alkoxy substituted with one or more
F (e.g., methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or
t-butoxy, each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.3 is selected from F,
C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each of which
is substituted with one or more F), and C.sub.1-C.sub.4 alkoxy
substituted with one or more F (e.g., methoxy, ethoxy, propoxy,
i-propoxy, butoxy, i-butoxy, or t-butoxy, each of which is
substituted with one or more F). In one embodiment, at least one
Z.sub.3 is selected from F, SF.sub.5, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.3 is selected from F, CF.sub.3, CHF.sub.2,
CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, CH.sub.2CH.sub.2F,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.3 is selected from F, CF.sub.3, CHF.sub.2,
CH.sub.2F, OCF.sub.3, OCHF.sub.2, and OCH.sub.2F. In one
embodiment, at least one Z.sub.3 is selected from F, CF.sub.3, and
OCF.sub.3. In one embodiment, at least one Z.sub.3 is selected from
F and C.sub.1-C.sub.4 alkyl substituted with one or more F (e.g.,
methyl, ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl, each
of which is substituted with one or more F). In one embodiment, at
least one Z.sub.3 is selected from F, SF.sub.5, CF.sub.3,
CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3, CH.sub.2CHF.sub.2, and
CH.sub.2CH.sub.2F. In one embodiment, at least one Z.sub.3 is
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CF.sub.3,
CH.sub.2CHF.sub.2, and CH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.3 is selected from F, CF.sub.3, CHF.sub.2, and
CH.sub.2F. In one embodiment, the phenyl is substituted with one or
more substituents independently selected from F and CF.sub.3. In
one embodiment, at least one Z.sub.3 is selected from F and
C.sub.1-C.sub.4 alkoxy substituted with one or more F (e.g.,
methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, or t-butoxy,
each of which is substituted with one or more F). In one
embodiment, at least one Z.sub.3 is selected from F, SF.sub.5,
OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CF.sub.3,
OCH.sub.2CHF.sub.2, and OCH.sub.2CH.sub.2F. In one embodiment, at
least one Z.sub.3 is selected from F, OCF.sub.3, OCHF.sub.2,
OCH.sub.2F, OCH.sub.2CF.sub.3, OCH.sub.2CHF.sub.2, and
OCH.sub.2CH.sub.2F. In one embodiment, at least one Z.sub.3 is
selected from F, CF.sub.3, CHF.sub.2, CH.sub.2F, OCF.sub.3,
OCHF.sub.2, and OCH.sub.2F. In one embodiment, at least one Z.sub.3
is selected from F and OCF.sub.3. In one embodiment, at least one
Z.sub.3 is F. In one embodiment, at least one Z.sub.3 is CH.sub.3.
In one embodiment, at least one Z.sub.3 is CF.sub.3. In one
embodiment, at least one Z.sub.3 is OCH.sub.3. In one embodiment,
at least one Z.sub.3 is OCF.sub.3. In one embodiment, at least one
Z.sub.3 is selected from C.sub.1-C.sub.4 alkyl (e.g., methyl,
ethyl, propyl, i-propyl, butyl, i-butyl, or t-butyl) and
C.sub.1-C.sub.4 alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,
butoxy, i-butoxy, or t-butoxy). In one embodiment, at least one
Z.sub.3 is selected from CH.sub.3, CH.sub.2CH.sub.3, OCH.sub.3, and
OCH.sub.2CH.sub.3. In one embodiment, at least one Z.sub.3 is
selected from CH.sub.3 and CH.sub.2CH.sub.3. In one embodiment, at
least one Z.sub.3 is CH.sub.3. In one embodiment, at least one
Z.sub.3 is selected from OCH.sub.3 and OCH.sub.2CH.sub.3. In one
embodiment, at least one Z.sub.3 is OCH.sub.3.
In one embodiment, a compound of the present application is
selected from the compounds in Table 1.
TABLE-US-00001 TABLE 1 Compound No. Structure 1 ##STR00011## 2
##STR00012## 3 ##STR00013## 4 ##STR00014## 5 ##STR00015## 6
##STR00016##
In one embodiment, a compound of the application is a
pharmaceutically acceptable salt. In one embodiment, a compound of
the application is a solvate. In one embodiment, a compound of the
application is a hydrate.
A "selective KCNQ2/3 channel modulator" or "selective KCNQ2/3
channel opener" can be identified, for example, by comparing the
ability of a compound to modulate KCNQ2/3 potassium channel (e.g.,
open KCNQ2/3 potassium channel) to its ability to modulate the
other potassium channels (e.g., open other potassium channels). For
example, a substance may be assayed for its ability to modulate
KCNQ2/3 potassium channel, KCNQ3/5 potassium channel, KCNQ4
potassium channel, and/or other potassium channels (e.g., open
KCNQ2/3 potassium channel, KCNQ3/5 potassium channel, KCNQ4
potassium channel, and/or other potassium channels). In some
embodiments, the selectivity can be identified by measuring the
EC.sub.50 or IC.sub.50 of the compounds.
In some embodiments, one or more of the compounds of the present
application modulate KCNQ2/3 potassium channel more selectively
over other potassium channels. In some embodiments, one or more of
the compounds of the present application are about 10%, about 20%,
about 30%, about 40%, about 50%, about 60%, about 70%, about 80%,
about 90%, or about 99% more selective at modulating KCNQ2/3
potassium channel (e.g., opening KCNQ2/3 potassium channel) more
selectively over other potassium channels (e.g., KCNQ3/5 potassium
channel and/or KCNQ4 potassium channel). In some embodiments, one
or more of the compounds of the present application are about 10%,
about 20%, about 30%, about 40%, or about 50% more selective at
modulating KCNQ2/3 potassium channel (e.g., opening KCNQ2/3
potassium channel) more selectively over other potassium channels
(e.g., KCNQ3/5 potassium channel and/or KCNQ4 potassium channel).
In some embodiments, one or more of the compounds of the present
application are about 20%, about 30%, about 40%, about 50%, or
about 60% more selective at modulating KCNQ2/3 potassium channel
(e.g., opening KCNQ2/3 potassium channel) more selectively over
other potassium channels (e.g., KCNQ3/5 potassium channel and/or
KCNQ4 potassium channel). In some embodiments, one or more of the
compounds of the present application are about 30%, about 40%,
about 50%, about 60%, or about 70% more selective at modulating
KCNQ2/3 potassium channel (e.g., opening KCNQ2/3 potassium channel)
more selectively over other potassium channels (e.g., KCNQ3/5
potassium channel and/or KCNQ4 potassium channel). In some
embodiments, one or more of the compounds of the present
application are about 40%, about 50%, about 60%, about 70%, or
about 80% more selective at modulating KCNQ2/3 potassium channel
(e.g., opening KCNQ2/3 potassium channel) more selectively over
other potassium channels (e.g., KCNQ3/5 potassium channel and/or
KCNQ4 potassium channel). In some embodiments, one or more of the
compounds of the present application are about 50%, about 60%,
about 70%, about 80%, or about 90% more selective at modulating
KCNQ2/3 potassium channel (e.g., opening KCNQ2/3 potassium channel)
more selectively over other potassium channels (e.g., KCNQ3/5
potassium channel and/or KCNQ4 potassium channel). In some
embodiments, one or more of the compounds of the present
application are about 60%, about 70%, about 80%, about 90%, or
about 99% more selective at modulating KCNQ2/3 potassium channel
(e.g., opening KCNQ2/3 potassium channel) more selectively over
other potassium channels (e.g., KCNQ3/5 potassium channel and/or
KCNQ4 potassium channel).
In some embodiments, one or more of the compounds of the present
application are between about 10% and about 99% more selective more
selective at modulating KCNQ2/3 potassium channel (e.g., open
KCNQ2/3 potassium channel) more selectively over other potassium
channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4 potassium
channel). In some embodiments, one or more of the compounds of the
present application are between about 10% and about 30% more
selective more selective at modulating KCNQ2/3 potassium channel
(e.g., open KCNQ2/3 potassium channel) more selectively over other
potassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4
potassium channel). In some embodiments, one or more of the
compounds of the present application are between about 20% and
about 40% more selective more selective at modulating KCNQ2/3
potassium channel (e.g., open KCNQ2/3 potassium channel) more
selectively over other potassium channels (e.g., KCNQ3/5 potassium
channel and/or KCNQ4 potassium channel). In some embodiments, one
or more of the compounds of the present application are between
about 30% and about 50% more selective more selective at modulating
KCNQ2/3 potassium channel (e.g., open KCNQ2/3 potassium channel)
more selectively over other potassium channels (e.g., KCNQ3/5
potassium channel and/or KCNQ4 potassium channel). In some
embodiments, one or more of the compounds of the present
application are between about 40% and about 60% more selective more
selective at modulating KCNQ2/3 potassium channel (e.g., open
KCNQ2/3 potassium channel) more selectively over other potassium
channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4 potassium
channel). In some embodiments, one or more of the compounds of the
present application are between about 50% and about 70% more
selective more selective at modulating KCNQ2/3 potassium channel
(e.g., open KCNQ2/3 potassium channel) more selectively over other
potassium channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4
potassium channel). In some embodiments, one or more of the
compounds of the present application are between about 60% and
about 80% more selective more selective at modulating KCNQ2/3
potassium channel (e.g., open KCNQ2/3 potassium channel) more
selectively over other potassium channels (e.g., KCNQ3/5 potassium
channel and/or KCNQ4 potassium channel). In some embodiments, one
or more of the compounds of the present application are between
about 70% and about 90% more selective more selective at modulating
KCNQ2/3 potassium channel (e.g., open KCNQ2/3 potassium channel)
more selectively over other potassium channels (e.g., KCNQ3/5
potassium channel and/or KCNQ4 potassium channel). In some
embodiments, one or more of the compounds of the present
application are between about 80% and about 99% more selective more
selective at modulating KCNQ2/3 potassium channel (e.g., open
KCNQ2/3 potassium channel) more selectively over other potassium
channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4 potassium
channel).
As used herein, "selective", "selective KCNQ2/3 channel modulator",
"selective KCNQ2/3 channel opener", or "selective KCNQ2/3 compound"
refers to a compound, e.g., a compound of the application, that
effectively modulates KCNQ2/3 potassium channel (e.g., opens
KCNQ2/3 potassium channel) to a greater extent than other potassium
channels (e.g., KCNQ3/5 potassium channel and/or KCNQ4 potassium
channel).
In some embodiments, the compounds of the application are KCNQ2/3
channel modulators that modulates KCNQ2/3 potassium channel (e.g.,
opens KCNQ2/3 potassium channel) with at least 2-fold, 3-fold,
5-fold, 10-fold, 25-fold, 50-fold or 100-fold selectivity over
other potassium channels (e.g., KCNQ3/5 potassium channel and/or
KCNQ4 potassium channel).
The present application relates to pharmaceutical compositions
comprising one of the compounds of the application as an active
ingredient. In one embodiment, the application provides a
pharmaceutical composition comprising at least one compound
disclosed herein (e.g., a compound of formula A, Ia, Ib, IIa, IIb,
IIIa, IIIb, IVa, or IVb), or a pharmaceutically acceptable salt or
solvate thereof, and one or more pharmaceutically acceptable
carrier or excipient. In one embodiment, the application provides a
pharmaceutical composition comprising at least one compound of
Table 1, or a pharmaceutically acceptable salt or solvate thereof,
and one or more pharmaceutically acceptable carrier or
excipient.
The present application relates to a method of synthesizing a
compound of the application or a pharmaceutically acceptable salt
or solvate thereof. A compound of the application can be
synthesized using a variety of methods known in the art, such as
those described in U.S. Pat. No. 8,916,133, the contents of which
are incorporated by reference in their entirety. The schemes and
description below depict general routes for the preparation of a
compound of the application. For example, compounds of the present
application can be synthesized by following the steps outlined in
Schemes 1-2 which comprise different sequences of assembling
intermediates 1a-1e and 2a-2f. Starting materials are either
commercially available or made by known procedures in the reported
literature or as illustrated.
##STR00017##
The general way of preparing representative compounds of the
present application using intermediates 1a-1e is outlined in Scheme
1. Nucleophilic addition of 1a to fluoride 1b in the presence of a
base (e.g., triethylamine (Et.sub.3N)) in a solvent (e.g.,
dimethylsulfoxide (DMSO)) and optionally at an elevated temperature
provides intermediate 1c. Methylation of 1c with a base (e.g.,
sodium hydride (NaH)) and an alkyltriphenylphosphonium salt (e.g.,
methyltriphenylphosphonium bromide (MePPh.sub.3Br)) in a solvent
(e.g., tetrahydrofuran (THF)) and optionally at an elevated
temperature provides intermediate 1d. Reduction of 1d using a metal
catalyst (e.g., Zinc (Zn)) and ammonium chloride (NH.sub.4Cl) in a
solvent (e.g., methanol (MeOH) and water (H.sub.2O)) and optionally
at an elevated temperature provides intermediate 1e. Acetylation of
1e with tert-butylacetyl chloride in the presence of a base (e.g.,
diisopropylethylamine (DIPEA)) in a solvent (e.g., dichloromethane
(DCM)) and optionally at an elevated temperature provides a
compound of formula Ia.
##STR00018##
The general way of preparing representative compounds of the
present application using intermediates 2a-2f is outlined in Scheme
2. Nucleophilic addition of 2a to fluoride 2b in the presence of a
base (e.g., triethylamine (Et.sub.3N)) in a solvent (e.g.,
dimethylsulfoxide (DMSO)) and optionally at an elevated temperature
provides intermediate 2c. Methylation of 2c with a base (e.g.,
sodium hydride (NaH)) and an alkyltriphenylphosphonium salt (e.g.,
methyltriphenylphosphonium bromide (MePPh.sub.3Br)) in a solvent
(e.g., tetrahydrofuran (THF)) and optionally at an elevated
temperature provides intermediate 2d. Reduction of 2d using a metal
catalyst (e.g., Zinc (Zn)) and ammonium chloride (NH.sub.4Cl) in a
solvent (e.g., methanol (MeOH) and water (H.sub.2O)) and optionally
at an elevated temperature provides intermediate 2e. Acetylation of
2e with tert-butylacetyl chloride in the presence of a base (e.g.,
diisopropylethylamine (DIPEA)) in a solvent (e.g., dichloromethane
(DCM)) and optionally at an elevated temperature provides
intermediate 2f. Deprotection of 2f in the presence of an acid
(e.g., hydrochloric acid (HCl)) in a solvent (e.g., dichloromethane
(DCM) and water (H.sub.2O)) and optionally at an elevated
temperature provides a compound of formula Iaa.
The present application also comprehends deuterium labeled
compounds, wherein one or more hydrogen atoms is replaced by a
deuterium atom having an abundance of deuterium at that position
that is substantially greater than the natural abundance of
deuterium, which is 0.015%.
Deuterium labeled compounds can be prepared by using any of a
variety of art-recognized techniques. For example, deuterium
labeled compounds of any of the formulae described herein and
compounds listed in Table 1 of this application can be
prepared.
In one aspect, a deuterium labeled compound of the application is a
pharmaceutically acceptable salt. In one aspect, a deuterium
labeled compound of the application is a solvate. In one aspect, a
deuterium labeled compound of the application is a hydrate.
The present application relates to pharmaceutical compositions
comprising one of the deuterium labeled compounds of the
application as an active ingredient. In one aspect, the application
provides a pharmaceutical composition comprising at least one
deuterium labeled compound of any of the formulae described herein
or a pharmaceutically acceptable salt or solvate thereof and one or
more pharmaceutically acceptable carrier or excipient.
The present application relates to a method of synthesizing a
deuterium labeled compound of the application or a pharmaceutically
acceptable salt or solvate thereof. The deuterium labeled compounds
of the application can be prepared using any of a variety of
art-recognized techniques, such as those described in U.S. Pat. No.
8,916,133, the contents of which are incorporated by reference in
their entirety. For example, a deuterium labeled compound can be
prepared by starting with deuterium labeled Compound 1 and/or
substituting a readily available deuterium labeled reagent for a
non-deuterium labeled reagent.
The scheme and description below depicts a general route for the
incorporation of deuterium label to produce a deuterium labeled
compound of the application.
##STR00019##
Scheme 1A outlines a preparation for a deuterium labeled compound
of the application. The preparation begins with Compound A (from
Scheme 1A described herein). In Step 1, the nitro group of Compound
A is reduced and then the deuterium label is introduced via
formation of a carbamate containing one or more deuterium. For
example, the nitro group of Compound A can be reduced using zinc
powder and ammonium chloride in methanol and the carbamate can be
formed using ethyl-d.sub.5 chloroformate to provide a deuterium
labeled compound.
In some embodiments, temporary protecting groups may be used to
prevent other reactive functionality, such as amines, thiols,
alcohols, phenols, and carboxylic acids, from participating or
interfering in the fluorination reaction. Representative amine
protecting groups include, for example, tert-butoxycarbonyl and
trityl (removed under acid conditions), Fmoc (removed by the use of
secondary amines such as piperidine), and benzyloxycarbonyl
(removed by strong acid or by catalytic hydrogenolysis). The trityl
group may also be used for the protection of thiols, phenols, and
alcohols. In certain embodiments the carboxylic acid protecting
groups include, for example, tert-butyl ester (removed by mild
acid), benzyl ester (usually removed by catalytic hydrogenolysis),
and alkyl esters such as methyl or ethyl (usually removed by mild
base). All protecting groups may be removed at the conclusion of
the synthesis using the conditions described above for the
individual protecting groups, and the final product may be purified
by techniques which would be readily apparent to one of ordinary
skill in the art, in combination with the teachings described
herein.
Biological Assays
Assessment of KCNQ2/3 Channel Activation Activity
Biological activities of the compounds of the application can be
assessed by using various methods known in the art. For example,
the KCNQ2/3 channel activation activity of the compounds of the
application can be evaluated through an in vitro assay described
below.
The in vitro effects of a compound of the application on cloned
KCNQ2/3 potassium channels (e.g., encoded by the human KCNQ2/3
gene) are evaluated using a patch clamp system. Compounds of the
application are tested at various concentrations (e.g., 0.01, 0.1,
1, 10 and 100 .mu.M) for a certain duration of exposure (e.g., 5
min). The baseline for each recording is established. A single test
compound concentration is applied for a certain duration of
exposure after the vehicle. Each recording ends with treatment with
a supramaximal dose of linopirdine. The % activation is calculated
using the following equation by using leak subtracted
responses:
##EQU00001## Maximal Electroshock Seizure Test (MES)
In MES test, the ability of different doses of the test compound in
preventing seizure induced by an electrical stimulus, delivered
through the corneal electrodes primed with a drop of
anesthetic/electrolyte solution is tested. Mice are restrained and
released immediately following corneal stimulation that allows for
the observation of the entire seizure episode. A maximal seizure in
a test animal includes four distinct phases that includes, hind leg
flexor component tonic phase (Phase I), hind leg extensor component
of the tonic phase (Phase II), intermittent, whole-body clonus
(Phase III), and muscular relaxation (Phase IV) followed by seizure
termination (Woodbury & Davenport, 1952; Racine et al., 1972).
Test compounds are tested for their ability to abolish hind limb
tonic extensor component that indicates the compound's ability to
inhibit MES-induced seizure spread. Compounds are pre-administered
(i.p) and tested at various time points for the abolishment of hind
limb tonic extensor component after electrical stimulus.
Corneal-Kindled Mouse Model of Partial Seizures
In corneal kindled seizure model, mice are kindled electrically
with stimulation delivered through corneal electrodes primed with
tetracaine hydrochloride in saline, twice daily, until 5
consecutive stage V seizures are induced. Mice are considered
kindled when they display at least 5 consecutive stage V seizures
according to the Racine scale (Racine et al., 1972) including,
mouth and facial clonus (stage I), Stage I plus head nodding (Stage
II), Stage II plus forelimb clonus (Stage III), Stage III plus
rearing (Stage IV), and stage IV plus repeated rearing and falling
(Stage V) (Racine et al., 1972). At the completion of the kindling
acquisition, mice are permitted a 3-day stimulation-free period
prior to any drug testing. On the day of the experiment, fully
kindled mice are pre-administered (i.p) with increasing doses of
the test compound and challenged with the corneal kindling
stimulus. Mice are scored as protected (seizure score of <3) or
not protected, (seizure score.gtoreq.4) based on the Racine scoring
(Racine et al., 1972).
Pharmaceutical Compositions
The present application relates to pharmaceutical compositions
comprising a compound of the application as an active ingredient.
In one embodiment, the application provides a pharmaceutical
composition comprising at least one compound of each of the
formulae described herein, or a pharmaceutically acceptable salt or
solvate thereof, and one or more pharmaceutically acceptable
carriers or excipients. In one embodiment, the application provides
a pharmaceutical composition comprising at least one compound
selected from Table 1.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified
amounts, as well as any product which results, directly or
indirectly, from combination of the specified ingredients in the
specified amounts.
The compounds of the application can be formulated for oral
administration in forms such as tablets, capsules (each of which
includes sustained release or timed release formulations), pills,
powders, granules, elixirs, tinctures, suspensions, syrups and
emulsions. The compounds of the application can also be formulated
for intravenous (bolus or in-fusion), intraperitoneal, topical,
subcutaneous, intramuscular or transdermal (e.g., patch)
administration, all using forms well known to those of ordinary
skill in the pharmaceutical arts.
The formulation of the present application may be in the form of an
aqueous solution comprising an aqueous vehicle. The aqueous vehicle
component may comprise water and at least one pharmaceutically
acceptable excipient. Suitable acceptable excipients include those
selected from the group consisting of a solubility enhancing agent,
chelating agent, preservative, tonicity agent, viscosity/suspending
agent, buffer, and pH modifying agent, and a mixture thereof.
Any suitable solubility enhancing agent can be used. Examples of a
solubility enhancing agent include cyclodextrin, such as those
selected from the group consisting of
hydroxypropyl-.beta.-cyclodextrin, methyl-.beta.-cyclodextrin,
randomly methylated-.beta.-cyclodextrin,
ethylated-.beta.-cyclodextrin, triacetyl-.beta.-cyclodextrin,
peracetylated-.beta.-cyclodextrin,
carboxymethyl-.beta.-cyclodextrin,
hydroxyethyl-.beta.-cyclodextrin,
2-hydroxy-3-(trimethylammonio)propyl-.beta.-cyclodextrin,
glucosyl-.beta.-cyclodextrin, sulphated .beta.-cyclodextrin
(S-.beta.-CD), maltosyl-.beta.-cyclodextrin, .beta.-cyclodextrin
sulfobutyl ether, branched-.beta.-cyclodextrin,
hydroxypropyl-.gamma.-cyclodextrin, randomly
methylated-.gamma.-cyclodextrin, and
trimethyl-.gamma.-cyclodextrin, and mixtures thereof.
Any suitable chelating agent can be used. Examples of a suitable
chelating agent include those selected from the group consisting of
ethylenediaminetetraacetic acid and metal salts thereof, disodium
edetate, trisodium edetate, and tetrasodium edetate, and mixtures
thereof.
Any suitable preservative can be used. Examples of a preservative
include those selected from the group consisting of quaternary
ammonium salts such as benzalkonium halides (preferably
benzalkonium chloride), chlorhexidine gluconate, benzethonium
chloride, cetyl pyridinium chloride, benzyl bromide, phenylmercury
nitrate, phenylmercury acetate, phenylmercury neodecanoate,
merthiolate, methylparaben, propylparaben, sorbic acid, potassium
sorbate, sodium benzoate, sodium propionate, ethyl
p-hydroxybenzoate, propylaminopropyl biguanide, and
butyl-p-hydroxybenzoate, and sorbic acid, and mixtures thereof.
The aqueous vehicle may also include a tonicity agent to adjust the
tonicity (osmotic pressure). The tonicity agent can be selected
from the group consisting of a glycol (such as propylene glycol,
diethylene glycol, triethylene glycol), glycerol, dextrose,
glycerin, mannitol, potassium chloride, and sodium chloride, and a
mixture thereof.
The aqueous vehicle may also contain a viscosity/suspending agent.
Suitable viscosity/suspending agents include those selected from
the group consisting of cellulose derivatives, such as methyl
cellulose, ethyl cellulose, hydroxyethylcellulose, polyethylene
glycols (such as polyethylene glycol 300, polyethylene glycol 400),
carboxymethyl cellulose, hydroxypropylmethyl cellulose, and
cross-linked acrylic acid polymers (carbomers), such as polymers of
acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol
(Carbopols--such as Carbopol 934, Carbopol 934P, Carbopol 971,
Carbopol 974 and Carbopol 974P), and a mixture thereof.
In order to adjust the formulation to an acceptable pH (typically a
pH range of about 5.0 to about 9.0, more preferably about 5.5 to
about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about
8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5
to about 8.0), the formulation may contain a pH modifying agent.
The pH modifying agent is typically a mineral acid or metal
hydroxide base, selected from the group of potassium hydroxide,
sodium hydroxide, and hydrochloric acid, and mixtures thereof, and
preferably sodium hydroxide and/or hydrochloric acid. These acidic
and/or basic pH modifying agents are added to adjust the
formulation to the target acceptable pH range. Hence it may not be
necessary to use both acid and base--depending on the formulation,
the addition of one of the acid or base may be sufficient to bring
the mixture to the desired pH range.
The aqueous vehicle may also contain a buffering agent to stabilize
the pH. When used, the buffer is selected from the group consisting
of a phosphate buffer (such as sodium dihydrogen phosphate and
disodium hydrogen phosphate), a borate buffer (such as boric acid,
or salts thereof including disodium tetraborate), a citrate buffer
(such as citric acid, or salts thereof including sodium citrate),
and .epsilon.-aminocaproic acid, and mixtures thereof.
The formulation may further comprise a wetting agent. Suitable
classes of wetting agents include those selected from the group
consisting of polyoxypropylene-polyoxyethylene block copolymers
(poloxamers), polyethoxylated ethers of castor oils,
polyoxyethylenated sorbitan esters (polysorbates), polymers of
oxyethylated octyl phenol (Tyloxapol), polyoxyl 40 stearate, fatty
acid glycol esters, fatty acid glyceryl esters, sucrose fatty
esters, and polyoxyethylene fatty esters, and mixtures thereof.
Oral compositions generally include an inert diluent or an edible
pharmaceutically acceptable carrier. They can be enclosed in
gelatin capsules or compressed into tablets. For the purpose of
oral therapeutic administration, the active compound can be
incorporated with excipients and used in the form of tablets,
troches, or capsules. Oral compositions can also be prepared using
a fluid carrier for use as a mouthwash, wherein the compound in the
fluid carrier is applied orally and swished and expectorated or
swallowed. Pharmaceutically compatible binding agents, and/or
adjuvant materials can be included as part of the composition. The
tablets, pills, capsules, troches and the like can contain any of
the following ingredients, or compounds of a similar nature: a
binder such as microcrystalline cellulose, gum tragacanth or
gelatin; an excipient such as starch or lactose, a disintegrating
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterotes; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring.
Methods of Use
The present application relates to methods for the use of compounds
of the application. The compounds of the application have a useful
pharmacological activity spectrum and are therefore particularly
suitable for the prophylaxis and/or treatment of diseases or
disorders.
The present application provides a method of treating or preventing
diseases or disorders, comprising administering a therapeutically
effective amount of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, to a subject
in need thereof. The present application also provides the use of a
compound of the application, or a pharmaceutically acceptable salt
or solvate thereof, for the preparation of a medicament for
administration to a subject for the treatment or prevention of
diseases or disorders. The present application also provides a
compound of the application, or a pharmaceutically acceptable salt
or solvate thereof, for treating or preventing diseases or
disorders.
In one embodiment, the disease or disorder is a condition which can
be ameliorated by KCNQ2/3 potassium channel opening. In one
embodiment, the disease or disorder is selected from epilepsy,
neurotransmission disorder, CNS disorder, neurodegenerative disease
(e.g., Alzheimer's disease, ALS, motor neuron disease, Parkinson's
disease, macular degeneration, or glaucoma), cognitive disorder
(e.g., degenerative dementia (including senile dementia,
Alzheimer's disease, Pick's disease, Huntington's chorea,
Parkinson's disease, and Creutzfeldt-Jakob disease); vascular
dementia (including multi-infarct dementia); dementia associated
with intracranial space occupying lesions, trauma, infections or
related conditions (including HIV infection), metabolism, toxins,
anoxia, or vitamin deficiency; mild cognitive impairment associated
with ageing, particularly Age Associated Memory Loss, or learning
deficiencies), bipolar disorder (e.g., Type I or II bipolar
disorder), unipolar depression, anxiety, migraine, ataxia,
myokimia, tinnitus, functional bowel disorders (e.g., non-ulcer
dyspepsia, non-cardiac chest pain, or irritable bowel syndrome),
cancer, inflammatory disease, ophthalmic disease (e.g., retinitis,
retinopathies, uveitis, or acute injury to the eye tissue), asthma,
allergic rhinitis, respiratory distress syndrome, gastrointestinal
conditions (e.g., inflammatory bowel disease, Chron's disease,
gastritis, irritable bowel syndrome, or ulcerative colitis), and
inflammation in such diseases as vascular disease, migraine,
periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's
disease, sclerodoma, type I diabetes, myasthenia gravis, multiple
sclerosis, sorcoidosis, nephrotic syndrome, Bechet's syndrome,
polymyositis, gingivitis, conjunctivitis, and myocardial
ischemia.
In one embodiment, the application provides a method of producing
an anti-epileptic, muscle relaxing, fever reducing, peripherally
analagesic, and/or anti-convulsive effect in a subject in need
thereof, comprising administering to the subject an effective
amount of a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof. The present application also
provides the use of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
producing an anti-epileptic, muscle relaxing, fever reducing,
peripherally analagesic, and/or anti-convulsive effect. The present
application also provides a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for producing
an anti-epileptic, muscle relaxing, fever reducing, peripherally
analagesic, and/or anti-convulsive effect.
In one embodiment, the application provides compounds that are
useful as an anti-convulsant. They are therefore useful in treating
or preventing epilepsy. Compounds of the application may be used to
improve the condition of a host, typically a human being, suffering
from epilepsy. They may be employed to alleviate the symptoms of
epilepsy in a host. "Epilepsy" is intended to include the following
seizures: simple partial seizures, complex partial seizures,
secondary generalized seizures, generalized seizures including
absence seizures, myoclonic seizures, clonic seizures, tonic
seizures, tonic clonic seizures and atonic seizures. Partial-onset
seizures are the most common type of seizure in adult patients. For
partial seizures, there is a focal epileptic zone (site of seizure
onset), and seizure activity is initially limited to one
hemisphere. Partial seizures can be further sub-divided into simple
partial (without impairment of consciousness), complex partial
(with impairment of consciousness with or following a simple
partial onset) and secondarily generalized (i.e., partial seizures,
either simple or complex, which evolve to generalized tonic-clonic
seizures). Simple partial seizures, depending on the anatomical
site of origin of the seizure, may have motor, somatosensory or
special sensory, autonomic or psychic signs or symptoms.
In one embodiment, the application provides a method of treating a
subject suffering from or susceptible to epilepsy, comprising
administering to the subject an effective amount of a compound of
the application or a pharmaceutically acceptable salt or solvate
thereof. The present application also provides the use of a
compound of the application, or a pharmaceutically acceptable salt
or solvate thereof, for the preparation of a medicament for
administration to a subject suffering from or susceptible to
epilepsy for the treatment of epilepsy. The present application
also provides a compound of the application, or a pharmaceutically
acceptable salt or solvate thereof, for treating a subject
suffering from or susceptible to epilepsy.
In one embodiment, the application provides a method for the
adjunctive treatment of adults with partial-onset seizures,
comprising administering to the subject an effective amount of a
compound of the application or a pharmaceutically acceptable salt
thereof. The present application also provides the use of a
compound of the application, or a pharmaceutically acceptable salt
or solvate thereof, for the preparation of a medicament for
adjunctive treatment of adults with partial-onset seizures. The
present application also provides a compound of the application, or
a pharmaceutically acceptable salt or solvate thereof, for
adjunctive treatment of adults with partial-onset seizures.
In one embodiment, the present application provides a method of
treating or preventing epilepsy, comprising administering a
therapeutically effective amount of a compound of the application,
or a pharmaceutically acceptable salt or solvate thereof, to a
subject in need thereof.
The present application also provides the use of a compound of the
application, or a pharmaceutically acceptable salt or solvate
thereof, for the preparation of a medicament for administration to
a subject for the treatment or prevention of epilepsy. The present
application also provides a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for treating
or preventing epilepsy.
In one embodiment, a compound of the application is administered in
combination with one or more anti-epileptic drugs (AEDs). There are
different types of AEDs. For example, narrow-spectrum AEDs include
phenytoin (Dilantin), phenobarbital, carbamazepine (Tegretol),
oxcarbazepine (Trileptal), gabapentin (Neurontin), pregabalin
(Lyrica), lacosamide (Vimpat), and vigabatrin (Sabril). Broad
spectrum AEDs include valproic acid (Depakote), lamotrigine
(Lamictal), topiramate (Topamax), zonisamide (Zonegran),
levetiracetam (Keppra), clonazepam (Klonopin), and rufinamide
(Banzel). In one embodiment, the AED is any AED. In one embodiment,
the AED is a narrow spectrum AED. In one embodiment, the AED is a
broad spectrum AED.
In one embodiment, the application provides compounds that are
useful as analgesics. The compounds are therefore useful in
treating or preventing pain. They may be used to improve the
condition of a host, typically a human being, suffering from pain.
They may be employed to alleviate pain in a host. Thus, the
compounds may be used as a pre-emptive analgesic to treat acute
pain such as musculoskeletal pain, post-operative pain and surgical
pain, chronic pain such as chronic inflammatory pain (e.g.,
rheumatoid arthritis and osteoarthritis), neuropathic pain (e.g.,
post herpetic neuralgia, trigeminal neuralgia and sympathetically
maintained pain) and pain associated with cancer and fibromyalgia.
The compounds may also be used in the treatment or prevention of
pain associated with migraine. The compounds may also be used in
the treatment of the pain (both chronic and acute), fever and
inflammation of conditions such as rheumatic fever; symptoms
associated with influenza or other viral infections, such as the
common cold; lower back and neck pain; headache; toothache; sprains
and strains; myositis; neuralgia; synovitis; arthritis, including
rheumatoid arthritis; degenerative joint diseases, including
osteoarthritis; gout and ankylosing spondylitis; tendinitis;
bursitis; skin related conditions, such as psoriasis, eczema, burns
and dermatitis; injuries, such as sports injuries and those arising
from surgical and dental procedures.
In one embodiment, the application provides a method of producing
an analgesic effect in a subject in need thereof, comprising
administering to the subject an effective amount of a compound of
the application or a pharmaceutically acceptable salt or solvate
thereof. The present application also provides the use of a
compound of the application, or a pharmaceutically acceptable salt
or solvate thereof, for the preparation of a medicament for
administration to a subject for producing an analgesic effect. The
present application also provides a compound of the application, or
a pharmaceutically acceptable salt or solvate thereof, for
producing an analgesic effect. In one embodiment, the analgesic
effect is a neuroprotective effect. In one embodiment, the
analgesic effect is a centrally acting analgesic effect.
In one embodiment, the application provides a method of treating or
preventing a neurotransmission disorder, CNS disorder,
neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor
neuron disease, Parkinson's disease, macular degeneration and
glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II
bipolar disorder), unipolar depression, or anxiety in a subject in
need thereof, comprising administering to the subject an effective
amount of a compound of the application or a pharmaceutically
acceptable salt or solvate thereof. The present application also
provides the use of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
treating or preventing a neurotransmission disorder, CNS disorder,
neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor
neuron disease, Parkinson's disease, macular degeneration and
glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II
bipolar disorder), unipolar depression, or anxiety. The present
application also provides a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for treating
or preventing a neurotransmission disorder, CNS disorder,
neurodegenerative disease (e.g., Alzheimer's disease, ALS, motor
neuron disease, Parkinson's disease, macular degeneration and
glaucoma), cognitive disorder, bipolar disorder (e.g., Type I or II
bipolar disorder), unipolar depression, or anxiety.
In one embodiment, the application provides a method of treating or
preventing migraine, ataxia, myokimia, tinnitus, and functional
bowel disorders (e.g., non-ulcer dyspepsia, non-cardiac chest pain,
or irritable bowel syndrome) in a subject in need thereof,
comprising administering to the subject an effective amount of a
compound of the application or a pharmaceutically acceptable salt
or solvate thereof. The present application also provides the use
of a compound of the application, or a pharmaceutically acceptable
salt or solvate thereof, for the preparation of a medicament for
administration to a subject for treating or preventing migraine,
ataxia, myokimia, tinnitus, and functional bowel disorders (e.g.,
non-ulcer dyspepsia, non-cardiac chest pain, or irritable bowel
syndrome). The present application also provides a compound of the
application, or a pharmaceutically acceptable salt or solvate
thereof, for treating or preventing migraine, ataxia, myokimia,
tinnitus, and functional bowel disorders (e.g., non-ulcer
dyspepsia, non-cardiac chest pain, or irritable bowel
syndrome).
In one embodiment, the application provides compounds that are
useful in the treatment of CNS disorders such as bipolar disorder,
alternatively known as manic depression. The compounds may thus be
used to improve the condition of a human patient suffering from
bipolar disorder. They may be used to alleviate the symptoms of
bipolar disorder in a host. The compounds may also be used in the
treatment of unipolar depression, ataxia, myokimia and anxiety.
In one embodiment, the application provides compounds that are
useful in the treatment of neurodegenerative diseases, such as
Alzheimer's disease, ALS, motor neuron disease, Parkinson's
disease, macular degeneration and glaucoma. The compounds of the
application may also be useful in neuroprotection and in the
treatment of neurodegeneration following stroke, cardiac arrest,
pulmonary bypass, traumatic brain injury, spinal cord injury or the
like. In one embodiment, compounds of the application are further
useful in the treatment of tinnitus.
In one embodiment, the application provides compounds that are
useful in the treatment of functional bowel disorders which include
non-ulcer dyspepsia, non-cardiac chest pain and in particular
irritable bowel syndrome. Irritable bowel syndrome is a
gastrointestinal disorder characterized by the presence of
abdominal pain and altered bowel habits without any evidence of
organic disease. The compounds may thus be used to alleviate pain
associated with irritable bowel syndrome. The condition of a human
patient suffering from irritable bowel syndrome may thus be
improved.
In one embodiment, the application provides a method of preventing
or reducing dependence on, or preventing or reducing tolerance, or
reverse tolerance, to a dependence-inducing agent in a subject in
need thereof, comprising administering to the subject an effective
amount of a compound of the application or a pharmaceutically
acceptable salt or solvate thereof. The present application also
provides the use of a compound of the application, or a
pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
preventing or reducing dependence on, or preventing or reducing
tolerance, or reverse tolerance, to a dependence-inducing agent.
The present application also provides a compound of the
application, or a pharmaceutically acceptable salt or solvate
thereof, for preventing or reducing dependence on, or preventing or
reducing tolerance, or reverse tolerance, to a dependence-inducing
agent. Examples of dependence inducing agents include opioids
(e.g., morphine), CNS depressants (e.g., ethanol), psychostimulants
(e.g., cocaine) and nicotine.
In one embodiment, the application provides a method of treating or
preventing cancer, inflammatory disease, or ophthalmic disease in a
subject in need thereof comprising administering to the subject an
effective amount of a compound of the application or a
pharmaceutically acceptable salt or solvate thereof. The present
application also provides the use of a compound of the application,
or a pharmaceutically acceptable salt or solvate thereof, for the
preparation of a medicament for administration to a subject for
treating or preventing cancer, inflammatory disease, or ophthalmic
disease. The present application also provides a compound of the
application, or a pharmaceutically acceptable salt or solvate
thereof, for treating or preventing cancer, inflammatory disease,
or ophthalmic disease.
In one embodiment, the application provides compounds that inhibit
cellular and neoplastic transformation and metastatic tumor growth
and hence are useful in the treatment of certain cancerous
diseases, such as colonic cancer.
In one embodiment, the application provides compounds that inhibit
inflammatory processes and therefore are of use in the treatment of
asthma, allergic rhinitis and respiratory distress syndrome;
gastrointestinal conditions such as inflammatory bowel disease,
Chron's disease, gastritis, irritable bowel syndrome and ulcerative
colitis; and the inflammation in such diseases as vascular disease,
migraine, periarteritis nodosa, thyroiditis, aplastic anemia,
Hodgkin's disease, sclerodoma, type I diabetes, myasthenia gravis,
multiple sclerosis, sorcoidosis, nephrotic syndrome, Bechet's
syndrome, polymyositis, gingivitis, conjunctivitis and myocardial
ischemia.
In one embodiment, the application provides compounds that are
useful in the treatment of ophthalmic diseases such as retinitis,
retinopathies, uveitis, and acute injury to the eye tissue.
In one embodiment, the application provides compounds that are
useful for the treatment of cognitive disorders such as dementia,
particularly degenerative dementia (including senile dementia,
Alzheimer's disease, Pick's disease, Huntington's chorea,
Parkinson's disease and Creutzfeldt-Jakob disease), and vascular
dementia (including multi-infarct dementia), as well as dementia
associated with intracranial space occupying lesions, trauma,
infections and related conditions (including HIV infection),
metabolism, toxins, anoxia and vitamin deficiency; and mild
cognitive impairment associated with ageing, particularly Age
Associated Memory Loss; and learning deficiencies.
In one embodiment, the application provides a method of producing
an anxiolytic effect in a subject in need thereof comprising
administering to the subject an effective amount of a compound of
the application or a pharmaceutically acceptable salt or solvate
thereof. In one embodiment, the application provides a method for
the treatment of anxiety and its related psychological and physical
symptoms. Anxiolytics have been shown to be useful in the treatment
of anxiety disorders. The present application also provides the use
of a compound of the application, or a pharmaceutically acceptable
salt or solvate thereof, for the preparation of a medicament for
administration to a subject for producing an anxiolytic effect. The
present application also provides a compound of the application, or
a pharmaceutically acceptable salt or solvate thereof, for
producing an anxiolytic effect.
In one embodiment, the application provides compounds for
treatment. In one embodiment, the application provides compounds
for prophylaxis. In one embodiment, the application provides
compound for alleviation of established symptoms.
Administration may for example be in the form of tablets, capsules,
pills, coated tablets, suppositories, ointments, gels, creams,
powders, dusting powders, aerosols or in liquid form. Liquid
application forms that may for example be considered are: oils or
alcoholic or aqueous solutions as well as suspensions and
emulsions. In one embodiment, the application provides forms of
application that are tablets that contain between 30 and 60 mg or
solutions that contain between 0.1 to 5 percent by weight of active
substance.
In one embodiment, a compound of the application is used in human
medicine. In one embodiment, the compound of the application is
used in veterinary medicine. In one embodiment, a compound of the
application is used in agriculture. In one embodiment, a compound
of the application is used alone or mixed with other
pharmacologically active substances.
The following Examples are illustrative and should not be
interpreted in any way so as to limit the scope of the
application.
EXAMPLES
Example 1: Synthesis of Compound 1
6-fluoro-2-(2,3,5,6-tetrafluoro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquinol-
ine
##STR00020##
Under air, to 1,2,3,4,5-pentafluoro-6-nitro-benzene (2.13 g, 10.0
mmol, 1.00 equiv) in DMSO (5 mL) at 0.degree. C. were added
6-fluoro-1,2,3,4-tetrahydroisoquinoline (1.51 g, 10.0 mmol, 1.00
equiv) and Et.sub.3N (1.67 mL, 12.0 mmol, 1.20 equiv). After
stirring for 30 min at 23.degree. C., the reaction mixture was
diluted with EtOAc (30 mL), washed with water (3.times.30 mL) and
brine (30 mL), and dried (MgSO.sub.4). The filtrate was
concentrated in vacuo and the residue was triturated with Et.sub.2O
to afford 2.40 g of the title compound (70% yield).
NMR Spectroscopy: .sup.1H NMR (400 MHz, CDCl.sub.3, 23.degree. C.,
.delta.): 7.04 (dd, J=7.8, 5.4 Hz, 1H), 6.96-6.87 (m, 2H), 4.59 (s,
2H), 3.67 (t, J=6.0 Hz, 2H), 3.02 (d, J=6.0 Hz, 2H).
2-(2,6-difluoro-3,5-dimethyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydroiso-
quinoline
##STR00021##
Under nitrogen, to methyltriphenylphosphonium bromide (24.9 g, 69.7
mmol, 10.0 equiv) in THF (350 mL) at 23.degree. C. was added NaH
(1.67 g, 69.7 mmol, 10.0 equiv). After stirring for 24 hr at
60.degree. C., the reaction mixture was cooled to 23.degree. C. and
6-fluoro-2-(2,3,5,6-tetrafluoro-4-nitrophenyl)-1,2,3,4-tetrahydroisoquino-
line (2.40 g, 6.97 mmol, 1.00 equiv) was added. After stirring for
48 hr at 60.degree. C., the reaction mixture was cooled to
23.degree. C. and water (500 mL) was added dropwise. The phases
were separated and the aqueous phase was extracted with EtOAc
(2.times.300 mL). The combined organic phases were washed with
brine (300 mL) and dried (MgSO.sub.4). The filtrate was
concentrated in vacuo and the residue was purified by column
chromatography on silica gel eluting with hexanes/EtOAc to afford
1.80 g of the title compound (77% yield).
NMR Spectroscopy: .sup.1H NMR (400 MHz, CDCl.sub.3, 23.degree. C.,
.delta.): 7.01 (dd, J=7.8, 5.4 Hz, 1H), 6.92-6.85 (m, 2H), 4.39 (s,
2H), 3.49 (t, J=6.0 Hz, 2H), 2.90 (d, J=6.0 Hz, 2H), 2.19 (s,
6H).
3,5-difluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2
(1H)-yl)-2,6-dimethylaniline
##STR00022##
Under air, to
2-(2,6-difluoro-3,5-dimethyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydrois-
oquinoline (1.90 g, 5.65 mmol, 1.00 equiv) in MeOH (57 mL) at
23.degree. C. were added Zn powder (1.85 g, 28.3 mmol, 5.00 equiv)
and NH.sub.4Cl (1.51 g, 28.3 mmol, 5.00 equiv) in H.sub.2O (10 mL).
After stirring for 1.5 hr at 23.degree. C., the reaction mixture
was filtered through a pad of celite. The filtrate was concentrated
in vacuo, and H.sub.2O (100 mL) and EtOAc (100 mL) were added to
the residue. The phases were separated and the aqueous phase was
extracted with EtOAc (2.times.100 mL). The combined organic phases
were washed with brine (200 mL) and dried (MgSO.sub.4). The
filtrate was concentrated in vacuo to afford crude aniline, which
was used in the next step without further purification.
N-(3,5-difluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2
(1H)-yl)-2,6-dimethylphenyl)-3,3-dimethylbutanamide (Compound
1)
##STR00023##
Under nitrogen, to
3,5-difluoro-4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2,6-dimethylani-
line obtained above in MeCN (6 mL) at 0.degree. C. were added DIPEA
(1.48 mL, 8.48 mmol, 1.50 equiv) and tert-butylacetyl chloride
(1.18 mL, 8.48 mmol, 1.50 equiv). After stirring for 1 hr at
23.degree. C., the reaction mixture was concentrated in vacuo, and
the residue was purified by column chromatography on silica gel
eluting with hexanes/EtOAc to afford 1.00 g of the title compound
(44% yield over 2 steps).
NMR Spectroscopy: .sup.1H NMR (400 MHz, CDCl.sub.3, 23.degree. C.,
.delta.): 6.98 (dd, J=7.8, 5.4 Hz, 1H), 6.90-6.80 (m, 2H), 6.64 (s,
1H), 4.30 (s, 2H), 3.43 (t, J=6.0 Hz, 2H), 2.95 (d, J=6.0 Hz, 2H),
2.30 (s, 2H), 2.10 (s, 6H), 1.16 (s, 9H).
Example 2: Synthesis of Compound 2
2,3,5,6-tetrafluoro-N-(4-fluorobenzyl)-4-nitroaniline
##STR00024##
Under air, to 1,2,3,4,5-pentafluoro-6-nitro-benzene (2.13 g, 10.0
mmol, 1.00 equiv) in DMSO (5 mL) at 0.degree. C. were added
4-fluorobenzylamine (1.25 g, 10.0 mmol, 1.00 equiv) and Et.sub.3N
(1.67 mL, 12.0 mmol, 1.20 equiv). After stirring for 30 min at
23.degree. C., the reaction mixture was diluted with EtOAc (30 mL),
washed with water (3.times.30 mL) and brine (30 mL), and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by chromatography on silica gel eluting with
hexanes/EtOAc to afford 1.85 g of the title compound (58%
yield).
NMR Spectroscopy: .sup.1H NMR (400 MHz, CDCl.sub.3, 23.degree. C.,
.delta.): 7.30 (dd, J=8.4, 5.4 Hz, 2H), 7.08 (dd, J=8.4, 8.4 Hz,
2H), 4.66 (s, 2H).
tert-butyl
4-fluorobenzyl(2,3,5,6-tetrafluoro-4-nitrophenyl)carbamate
##STR00025##
Under nitrogen, to
2,3,5,6-tetrafluoro-N-(4-fluorobenzyl)-4-nitroaniline (1.85 g, 5.81
mmol, 1.00 equiv) in THF (35 mL) at 23.degree. C. were added DMAP
(71 mg, 0.58 mmol, 10 mol %), NaH (153 mg, 6.39 mmol, 1.10 equiv),
and Boc.sub.2O (1.47 mL, 6.39 mmol, 1.10 equiv). After stirring for
1.5 hr at 60.degree. C., the reaction mixture was cooled to
23.degree. C. and water (20 mL) was added dropwise. The phases were
separated and the aqueous phase was extracted with EtOAc
(2.times.20 mL). The combined organic phases were washed with brine
(20 mL) and dried (MgSO.sub.4). The filtrate was concentrated in
vacuo and the residue was purified by column chromatography on
silica gel eluting with hexanes/EtOAc to afford 1.50 g of the title
compound (62% yield).
NMR Spectroscopy: .sup.1H NMR (400 MHz, CDCl.sub.3, 23.degree. C.,
.delta.): 7.20 (dd, J=8.4, 5.4 Hz, 2H), 6.98 (dd, J=8.4, 8.4 Hz,
2H), 4.81 (s, 2H), 1.44 (br s, 9H).
tert-butyl (2,6-difluoro-3,5-dimethyl-4-nitrophenyl)
(4-fluorobenzyl)carbamate
##STR00026##
Under nitrogen, to methyltriphenylphosphonium bromide (12.8 g, 35.9
mmol, 10.0 equiv) in THF (250 mL) at 23.degree. C. was added NaH
(862 mg, 35.9 mmol, 10.0 equiv). After stirring for 24 hr at
60.degree. C., the reaction mixture was cooled to 23.degree. C. and
tert-butyl
4-fluorobenzyl(2,3,5,6-tetrafluoro-4-nitrophenyl)carbamate (1.50 g,
3.59 mmol, 1.00 equiv) was added. After stirring for 48 hr at
60.degree. C., the reaction mixture was cooled to 23.degree. C. and
water (300 mL) was added dropwise. The phases were separated and
the aqueous phase was extracted with EtOAc (2.times.200 mL). The
combined organic phases were washed with brine (300 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by column chromatography on silica gel eluting
with hexanes/EtOAc to afford 1.06 g of the title compound (72%
yield).
NMR Spectroscopy: .sup.1H NMR (400 MHz, CDCl.sub.3, 23.degree. C.,
.delta.): 7.22-7.18 (m, 2H), 7.02-6.89 (m, 2H), 4.73 (s, 2H, major
isomer), 4.67 (s, 2H, minor isomer), 2.14 (br s, 6H), 1.50 (s, 9H,
minor isomer), 1.39 (s, 9H, major isomer). *A mixture of rotational
isomers was observed in the NMR time scale, which complicated the
further structural analysis.
tert-butyl (4-amino-2,6-difluoro-3,5-dimethylphenyl)
(4-fluorobenzyl)carbamate
##STR00027##
Under air, to
2-(2,6-difluoro-3,5-dimethyl-4-nitrophenyl)-6-fluoro-1,2,3,4-tetrahydrois-
oquinoline (1.06 g, 2.58 mmol, 1.00 equiv) in MeOH (26 mL) at
23.degree. C. were added Zn powder (844 mg, 12.9 mmol, 5.00 equiv)
and NH.sub.4Cl (690 mg, 12.9 mmol, 5.00 equiv) in H.sub.2O (5 mL).
After stirring for 1.5 hr at 23.degree. C., the reaction mixture
was filtered through a pad of celite. The filtrate was concentrated
in vacuo, and H.sub.2O (100 mL) and EtOAc (100 mL) were added to
the residue. The phases were separated and the aqueous phase was
extracted with EtOAc (2.times.100 mL). The combined organic phases
were washed with brine (200 mL) and dried (MgSO.sub.4). The
filtrate was concentrated in vacuo to afford crude aniline, which
was used in the next step without further purification.
tert-butyl
(4-(3,3-dimethylbutanamido)-2,6-difluoro-3,5-dimethylphenyl)
(4-fluorobenzyl)carbamate
##STR00028##
Under nitrogen, to tert-butyl
(4-amino-2,6-difluoro-3,5-dimethylphenyl)(4-fluorobenzyl)carbamate
obtained above in MeCN (4 mL) at 0.degree. C. were added DIPEA
(0.674 mL, 3.87 mmol, 1.50 equiv) and tert-butylacetyl chloride
(0.538 mL, 3.87 mmol, 1.50 equiv). After stirring for 1 hr at
23.degree. C., the reaction mixture was concentrated in vacuo to
afford crude acylation product, which was used in the next step
without further purification.
N-(3,5-difluoro-4-((4-fluorobenzyl)amino)-2,6-dimethylphenyl)-3,3-dimethyl-
butanamide (Compound 2)
##STR00029##
Under nitrogen, to tert-butyl
(4-(3,3-dimethylbutanamido)-2,6-difluoro-3,5-dimethylphenyl)(4-fluorobenz-
yl)carbamate obtained above in DCM (13 mL) at 23.degree. C. was
added HCl (2.0 M in Et.sub.2O, 12.9 mL, 25.8 mmol, 10.0 equiv).
After stirring for 3 hr at 23.degree. C., NaHCO.sub.3 (aq) (20 mL)
was added to the reaction mixture. The phases were separated and
the aqueous phase was extracted with EtOAc (2.times.20 mL). The
combined organic phases were washed with brine (20 mL) and dried
(MgSO.sub.4). The filtrate was concentrated in vacuo and the
residue was purified by column chromatography on silica gel eluting
with hexanes/EtOAc to afford 670 mg of the title compound (69%
yield over 3 steps).
NMR Spectroscopy: .sup.1H NMR (300 MHz, methanol-d4, 23.degree. C.,
.delta.): 7.31 (dd, J=8.4, 5.4 Hz, 2H), 6.98 (dd, J=8.4, 8.4 Hz,
2H), 4.40 (s, 2H), 2.27 (s, 2H), 2.02 (br s, 6H), 1.10 (s, 9H).
Example 3: Synthesis of Compound 3
Compound 3 is synthesized in a similar way as Compound 1 using the
corresponding commercially available 4-methoxypiperidine in place
of 6-fluoro-1,2,3,4-tetrahydroisoquinoline.
Example 4: Synthesis of Compound 4
Compound 4 is synthesized in a similar way as Compound 1 using the
corresponding commercially available ethyltriphenylphosphonium
bromide in place of methyltriphenylphosphonium bromide.
Example 5: Synthesis of Compound 5
Compound 5 is synthesized in a similar way as Compound 2 using the
corresponding commercially available ethyltriphenylphosphonium
bromide in place of methyltriphenylphosphonium bromide.
Example 6: Synthesis of Compound 6
Compound 6 is synthesized in a similar way as Compound 3 using the
corresponding commercially available ethyltriphenylphosphonium
bromide in place of methyltriphenylphosphonium bromide.
Example 7: Assessment of Recombinantly Expressed Human Kv7.2/7.3
Channels Activation Ability
The in vitro effects of a compound of the present application
recombinantly expressed human Kv7.2/7.3 channels are assessed on
Syncropatch high throughput electrophysiology platform.
Cell Preparations:
CHO cells stably expressing human Kv7.2/7.3 channels were cultured
in Ham's F-12 media (Hyclone, Cat # SH30022.02) supplemented with
10% Fetal Bovine Serum, 1.times.MEM non-essential amino acids, and
400 .mu.g/ml G418 at 37.degree. C. in 5% CO.sub.2. On the day of
Syncropatch, the cells were washed once in DPBS (Hyclone, Cat #
SH30028.03) for approximately 30 seconds. 1 ml of 1.times.0.015%
Trypsin-EDTA GIBCO Cat #25300-054) was added and swirled around to
cover the bottom of the flask, and allowed to sit on the cells for
about 4 minutes (approximately 90% of the cells were lifted by
light tapping of the flask). 10 ml of cold media (Ham's F-12 media
(Hyclone, Cat # SH30022.02) supplemented with 10% Fetal Bovine
Serum, 1.times.MEM non-essential amino acids, and 400 .mu.g/ml
G418) was added to inactivate Trypsin. The cells were then
triturated until a single cell suspension was achieved, and the
cell count was performed. The cells were then diluted to a
concentration of 5.times.10.sup.5/ml and placed into the "cell
hotel" on the deck of the Syncropatch at 10.degree. C. for about 1
hour to recover. 40 .mu.L of the cell suspension was dispensed into
each well of a 384-well Syncropatch chip by the onboard pipettor at
the beginning of each Syncropatch assay.
Test Solution Preparations.
The compounds to be tested were dissolved in DMSO to give 10 mM
stock solutions. Eight-point dose response curves were created by
performing semi-log serial dilutions from 10 mM compound stock
solutions in 100% DMSO. Concentration-response curves were
transferred to assay plates to give two-fold final compound
concentration to account for the two-fold dilution with drug
addition on the SyncroPatch. Final DMSO concentration in the assay
was 0.3%. Final assay test concentrations were 30 .mu.M to 0.01
.mu.M or 1 .mu.M to 0.0003 .mu.M. Negative (0.3% DMSO) and positive
(30 .mu.M ML213) controls were included in each test run to assess
pharmacological responsiveness.
Assessment Protocol:
Electrophysiological studies of the compounds were performed using
the Nanion SyncroPatch automated patch clamp platform. Compound
effects on Kv7 channels were assayed using a voltage protocol as
shown in FIG. 1.
Kv7 channels were evaluated using a voltage protocol in which cells
were voltage-clamped at a holding potential of -110 mV. Potassium
currents were activated with a series of voltage steps from -110 mV
to +50 mV in 10 mV intervals with 5.5 seconds between successive
voltage steps. Each voltage step was 3 seconds in duration and
immediately followed by a 1 second voltage step to -120 mV to
generate an inward "tail" current to allow construction of
activation (G-V) curves by plotting normalized peak tail current
versus the potential of the activating voltage step. To obtain
normalized values, peak current amplitudes for successive
depolarizing pulses were normalized against the maximum tail
current amplitude generated at +50 mV (Tatulian et al., Journal of
Neuroscience 2001, 21 (15)).
Data Analysis:
Data was collected on the Syncropatch platform using PatchControl
software (Nanion) and processed and analyzed using DataControl
Software (Nanion). Normalized percent activation was calculated and
activation curves were fit with a Boltzmann function to determine
the midpoint voltage of activation (G-V midpoint) for both
pre-compound and post-compound conditions for each of the 384-wells
of a sealchip with Pipeline Pilot (Accelrys). The difference in G-V
midpoint between pre-compound and post-compound conditions (.DELTA.
V0.5) was plotted as a function of concentration and
concentration-response curves were fit with a three-parameter
logistic equation {Y=Bottom+(Top-Bottom)/(1+10{circumflex over (
)}(Log EC50-X))} for determination of the EC.sub.50 (Graphpad
Prism).
Assessment Results:
Exemplary compounds of the present application were tested for
their ability to produce a concentration-dependent hyperpolarizing
shift in the midpoint of activation for heteromeric Kv7.2/7.3
channels. Eight of the compounds produced a quantifiable
hyperpolarizing shift in activation as determined by a
concentration-dependent shift in the midpoint that could be fit
with a 3-parameter logistic equation. These data were combined with
the initial 8-point concentration-response data in a single fit.
Potency and efficacy data for each compound are summarized in Table
2.
TABLE-US-00002 TABLE 2 Selectivity KCNQ3/ KCNQ4 5 EC50 EC50
Compound KCNQ2/3 KCNQ3/5 KCNQ4 KCNQ2/ KCNQ2/ No. EC.sub.50
EC.sub.50 EC.sub.50 3 EC50 3 EC50 Control A A B I IV 1 B C D III VI
2 A B C IV V A: <0.1 .mu.M, B: 0.1 to <1 .mu.M, C: 1 to
<10 .mu.M, D: .gtoreq.10 .mu.M. I: <1, II: 1 to <5, III: 5
to <10, IV: 10 to <50, V: 50 to <100, VI: .gtoreq.100.
##STR00030##
EQUIVALENTS
Those skilled in the art will recognize, or be able to ascertain,
using no more than routine experimentation, numerous equivalents to
the specific embodiments described specifically herein. Such
equivalents are intended to be encompassed in the scope of the
following claims.
* * * * *